A whole-cell pertussis vaccine engineered to elicit reduced reactogenicity protects baboons against pertussis challenge.

Whole-cell pertussis (wP) vaccines introduced in the 1940s led to a dramatic reduction of pertussis incidence and are still widely used in low- and middle-income countries (LMICs) worldwide. The reactogenicity of wP vaccines resulted in reduced public acceptance, which drove the development and introduction of acellular pertussis (aP) vaccines in high-income countries in the 1990s. Increased incidence of pertussis disease has been observed in high-income countries following the introduction of aP vaccines despite near universal rates of pediatric vaccination.

The contribution of BvgR, RisA, and RisS to global gene regulation, intracellular cyclic-di-GMP levels, motility, and biofilm formation in .

is a highly contagious respiratory bacterial veterinary pathogen. In this study the contribution of the transcriptional regulators BvgR, RisA, RisS, and the phosphorylation of RisA to global gene regulation, intracellular cyclic-di-GMP levels, motility, and biofilm formation were evaluated. Next Generation Sequencing (RNASeq) was used to differentiate the global gene regulation of both virulence-activated and virulence-repressed genes by each of these factors.

Repeated Bordetella pertussis Infections Are Required to Reprogram Acellular Pertussis Vaccine-Primed Host Responses in the Baboon Model.

Background: The United States has experienced a resurgence of pertussis following the introduction of acellular pertussis (aP) vaccines. This is likely due to the failure of aP vaccines to induce durable immunity and prevent infection, carriage, and transmission.

Methods: To evaluate the impact of aP vaccination on the immune response to infection and test the ability of infection to reprogram aP-imprinted immune responses, we challenged unvaccinated and aP-vaccinated baboons with Bordetella pertussis multiple times and accessed the immune responses and outcomes of infections after each exposure.

T cell reactivity to Bordetella pertussis is highly diverse regardless of childhood vaccination.

The incidence of whooping cough due to Bordetella pertussis (BP) infections has increased recently. It is believed that the shift from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines may be contributing to this rise. While T cells are key in controlling and preventing disease, nearly all knowledge relates to antigens in aP vaccines.

Genome-wide characterization of T cell responses to reveals broad reactivity and similar polarization irrespective of childhood vaccination profiles.

The incidence of whooping cough (pertussis), the respiratory disease caused by (BP) has increased in recent years, and it is suspected that the switch from whole-cell pertussis (wP) to acellular pertussis (aP) vaccines may be a contributing factor to the rise in morbidity. While a growing body of evidence indicates that T cells play a role in the control and prevention of symptomatic disease, nearly all data on human BP-specific T cells is related to the four antigens contained in the aP vaccines, and data detailing T cell responses to additional non-aP antigens, are lacking. Here, we derived a full-genome map of human BP-specific CD4+ T cell responses using a high-throughput Activation Induced Marker (AIM) assay, to screen a peptide library spanning over 3000 different BP ORFs.

Antigen Discovery for Next-Generation Pertussis Vaccines Using Immunoproteomics and Transposon-Directed Insertion Sequencing.

Background: Despite high vaccination rates, the United States has experienced a resurgence in reported cases of pertussis after switching to the acellular pertussis vaccine, indicating a need for improved vaccines that enhance infection control.

Methods: Bordetella pertussis antigens recognized by convalescent-baboon serum and nasopharyngeal wash were identified by immunoproteomics and their subcellular localization predicted. Genes essential or important for persistence in the baboon airway were identified by transposon-directed insertion-site sequencing (TraDIS) analysis.

Tracheal colonization factor A (TcfA) is a biomarker for rapid and specific detection of Bordetella pertussis.

Pertussis is a highly contagious disease for which prompt, point-of-care diagnosis remains an unmet clinical need. Results from conventional test modalities (nucleic acid detection, serology, and culture) take hours to days. To overcome this challenge, we identified a new biomarker (tracheal colonization factor A, TcfA) for detection of Bordetella pertussis infection by lateral flow immunoassay (LFIA).

Development and Validation of a Whole-Genome Screening Strategy.

The immune response elicited by the protective whole-cell pertussis (wP) versus the less-protective acellular pertussis (aP) vaccine has been well characterized; however, important clinical problems remain unsolved, as the inability of the currently administered aP vaccine is resulting in the reemergence of clinical disease (i.e., whooping cough).

Pertussis Toxin: A Key Component in Pertussis Vaccines?

is a human-specific pathogen and the causative agent of whooping cough. The ongoing resurgence in pertussis incidence in high income countries is likely due to faster waning of immunity and increased asymptomatic colonization in individuals vaccinated with acellular pertussis (aP) vaccine relative whole-cell pertussis (wP)-vaccinated individuals. This has renewed interest in developing more effective vaccines and treatments and, in support of these efforts, defining pertussis vaccine correlates of protection and the role of vaccine antigens and toxins in disease.

Asymptomatic Infection and Transmission of Pertussis in Households: A Systematic Review.

We conducted a systematic review to describe the frequency of mild, atypical, and asymptomatic infection among household contacts of pertussis cases and to explore the published literature for evidence of asymptomatic transmission. We included studies that obtained and tested laboratory specimens from household contacts regardless of symptom presentation and reported the proportion of cases with typical, mild/atypical, or asymptomatic infection. After screening 6789 articles, we included 26 studies.

Pertussis vaccines and protective immunity.

Despite high vaccine coverage, reported cases of pertussis have increased steadily over the last twenty years. This resurgence has stimulated interest in host responses to pertussis infection and vaccination with the goal of developing more effective next-generation vaccines and vaccination strategies. Optimal protection against Bordetella pertussis appears to be multifactorial requiring both humoral and cellular responses.

Histopathology of Bordetella pertussis in the Baboon Model.

Pertussis is a severe respiratory disease caused by The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, posttussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under 2 months of age experience more severe disease, with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases.

Maternal Vaccination With a Monocomponent Pertussis Toxoid Vaccine Is Sufficient to Protect Infants in a Baboon Model of Whooping Cough.

Background: Bordetella pertussis is a human pathogen responsible for serious respiratory illness. The disease is most severe in infants too young to be vaccinated with most hospitalizations and deaths occurring within this age group. The Advisory Committee on Immunization Practices recommended immunization of pregnant women to protect infants from birth until their first vaccination at 6-8 weeks of age.

Activation of Bvg-Repressed Genes in Bordetella pertussis by RisA Requires Cross Talk from Noncooperonic Histidine Kinase RisK.

The two-component response regulator RisA, encoded by open reading frame BP3554 in the Tohama I genomic sequence, is a known activator of genes, a set of genes whose expression is increased under the same environmental conditions (known as modulation) that result in repression of the virulence regulon. Here we demonstrate that RisA is phosphorylated and that RisA phosphorylation is required for activation of genes. An adjacent histidine kinase gene, , is truncated by frameshift mutation in but not in or Neither deletion of ' or nor phenotypic modulation with MgSO affected levels of phosphorylated RisA (RisA∼P) in However, RisA phosphorylation did require the histidine kinase encoded by BP3223, here named RisK (cognate histidine kinase of RisA).

Pertussis disease and transmission and host responses: insights from the baboon model of pertussis.

Whooping cough is a highly contagious, acute respiratory disease, caused by the Gram-negative bacterium Bordetella pertussis (Bp). Despite the introduction and widespread use of vaccines starting in the 1950s pertussis cases continue to be reported, with a significant global impact. The role of specific virulence factors in disease and the immune mechanisms associated with protection following natural infection or vaccination are still not completely understood.

Use of a Toxin Neutralization Assay To Characterize the Serologic Response to Adenylate Cyclase Toxin after Infection with Bordetella pertussis.

Adenylate cyclase toxin (ACT) is an essential virulence factor of Bordetella pertussis, and antibodies to ACT protect against B. pertussis infection in mice. The toxin is therefore a strong candidate antigen for addition to future acellular pertussis vaccines.

Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development.

Pertussis is a severe respiratory disease caused by infection with the bacterial pathogen Bordetella pertussis The disease affects individuals of all ages but is particularly severe and sometimes fatal in unvaccinated young infants. Other Bordetella species cause diseases in humans, animals, and birds. Scientific, clinical, public health, vaccine company, and regulatory agency experts on these pathogens and diseases gathered in Buenos Aires, Argentina from 5 to 8 April 2016 for the 11th International Bordetella Symposium to discuss recent advances in our understanding of the biology of these organisms, the diseases they cause, and the development of new vaccines and other strategies to prevent these diseases.

The multifaceted RisA regulon of Bordetella pertussis.

The whooping cough agent Bordetella pertussis regulates the production of its virulence factors by the BvgA/S system. Phosphorylated BvgA activates the virulence-activated genes (vags) and represses the expression of the virulence-repressed genes (vrgs) via the activation of the bvgR gene. In modulating conditions, with MgSO4, the BvgA/S system is inactive, and the vrgs are expressed.

Comparison of Three Whole-Cell Pertussis Vaccines in the Baboon Model of Pertussis.

Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have escalated since the 1990s and reached a 50-year high of 48,000 cases in 2012. While this pertussis resurgence is not completely understood, we previously showed that the current acellular pertussis vaccines do not prevent colonization or transmission following challenge.

Bordetella pertussis transmission.

Bordetella pertussis and B. bronchiseptica are Gram-negative bacterial respiratory pathogens. Bordetella pertussis is the causative agent of whooping cough and is considered a human-adapted variant of B.

Complete Genome Sequence of Bordetella pertussis D420.

Bordetella pertussis is the causative agent of whooping cough, a highly contagious, acute respiratory illness that has seen resurgence despite the use of vaccines. We present the complete genome sequence of a clinical strain of B. pertussis, D420, which is representative of a currently circulating clade of this pathogen.

The baboon model of pertussis: effective use and lessons for pertussis vaccines.

The USA is experiencing a pertussis resurgence that resulted in a 60-year high of 48,000 cases in 2012. Our ability to counteract this resurgence is hampered by the fact that pertussis pathogenesis and immunity to pertussis infection are not well studied. Studies in humans are difficult due to the low frequency of pertussis in the population, the cyclical nature of incidence and the sporadic geographic distribution of cases.