Qiushui He

Bordetella pertussis Strains with Increased Toxin Production Associated with Pertussis Resurgence

A more virulent strain of the disease is emerging.

Global Population Structure and Evolution of Bordetella pertussis and Their Relationship with Vaccination

ABSTRACT Bordetella pertussis causes pertussis, a respiratory disease that is most severe for infants. Vaccination was introduced in the 1950s, and in recent years, a resurgence of disease was observed worldwide, with significant mortality in infants. Possible causes for this include the switch from whole-cell vaccines (WCVs) to less effective acellular vaccines (ACVs), waning immunity, and pathogen adaptation. Pathogen adaptation is suggested by antigenic divergence between vaccine strains and circulating strains and by the emergence of strains with increased pertussis toxin production. We applied comparative genomics to a worldwide collection of 343 B. pertussis strains isolated between 1920 and 2010. The global phylogeny showed two deep branches; the largest of these contained 98% of all strains, and its expansion correlated temporally with the first descriptions of pertussis outbreaks in Europe in the 16th century. We found little evidence of recent geographical clustering of the strains within this lineage, suggesting rapid strain flow between countries. We observed that changes in genes encoding proteins implicated in protective immunity that are included in ACVs occurred after the introduction of WCVs but before the switch to ACVs. Furthermore, our analyses consistently suggested that virulence-associated genes and genes coding for surface-exposed proteins were involved in adaptation. However, many of the putative adaptive loci identified have a physiological role, and further studies of these loci may reveal less obvious ways in which B. pertussis and the host interact. This work provides insight into ways in which pathogens may adapt to vaccination and suggests ways to improve pertussis vaccines. IMPORTANCE Whooping cough is mainly caused by Bordetella pertussis, and current vaccines are targeted against this organism. Recently, there have been increasing outbreaks of whooping cough, even where vaccine coverage is high. Analysis of the genomes of 343 B. pertussis isolates from around the world over the last 100 years suggests that the organism has emerged within the last 500 years, consistent with historical records. We show that global transmission of new strains is very rapid and that the worldwide population of B. pertussis is evolving in response to vaccine introduction, potentially enabling vaccine escape. Whooping cough is mainly caused by Bordetella pertussis, and current vaccines are targeted against this organism. Recently, there have been increasing outbreaks of whooping cough, even where vaccine coverage is high. Analysis of the genomes of 343 B. pertussis isolates from around the world over the last 100 years suggests that the organism has emerged within the last 500 years, consistent with historical records. We show that global transmission of new strains is very rapid and that the worldwide population of B. pertussis is evolving in response to vaccine introduction, potentially enabling vaccine escape.

Factors contributing to pertussis resurgence

Despite extensive immunization, the disease pertussis remains one of the worlds leading causes of vaccine-preventable deaths. An estimated 50 million cases and 300,000 deaths occur every year. A resurgence of pertussis is observed in highly immunized populations. Increasing numbers of pertussis are reported in adolescents and adults who transmit bacteria to newborns and infants to whom pertussis may be a life-threatening disease. Many studies have shown that the causes for the resurgence are multiple, such as increased awareness of disease, use of better diagnostic tools, improved surveillance methods and waning vaccine-induced immunity. Recently, antigenic divergence has been found between vaccine strains and clinical isolates in many countries with high vaccination coverage. Here, we summarize these findings and discuss the factors contributing to pertussis resurgence in immunized populations.

Immunity to pertussis 5 years after booster immunization during adolescence.

BACKGROUND We conducted a 5-year follow-up study on the persistence of pertussis-specific antibody and cell-mediated immunity after booster immunization of adolescents aged 11-13 years with a tricomponent acellular pertussis vaccine (Boostrix; trials diphtheria-tetanus-acellular pertussis [Tdap]-004/030). METHODS Cellular and humoral immunity to pertussis toxin (PT), filamentous hemagglutinin, and pertactin were measured in adolescents (age, 16 years) 5 years after booster immunization. Similar investigations were performed for control adolescents who had received only diphtheria and tetanus booster vaccination. RESULTS Five years after pertussis booster vaccination, the geometric mean concentrations of immunoglobulin G (IgG) elicited by each of the 3 pertussis vaccine antigens decreased from 1-month and 3-year postvaccination levels, but with the exception of PT IgG, were still higher than the prevaccination levels. PT IgG levels were undetectable in 28% of the subjects, but 44% of those subjects still tested positive for cell-mediated immunity to PT. Filamentous hemagglutinin IgG and pertactin IgG levels were significantly higher in Tdap-boosted adolescents than in the control subjects. Antibody concentrations at 1 month after vaccination strongly predicted antibody persistence. Cell-mediated immunity levels to PT, filamentous hemagglutinin, and pertactin persisted above the prebooster levels measured 5 years earlier. CONCLUSIONS The results of the present study of adolescents indicate that the interval between acellular pertussis booster immunizations might be extended beyond 5 years.

Decennial Administration of a Reduced Antigen Content Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine in Young Adults

BACKGROUND Booster vaccination against tetanus and diphtheria at 10-year intervals is commonly recommended. Reduced antigen content diphtheria and tetanus toxoids and acellular pertussis (dTpa) vaccines developed for booster vaccination of preschool children, adolescents, and adults are licensed for once-in-a-lifetime use in most countries. Objective. To evaluate decennial administration of a dTpa vaccine. Methods. Young adults vaccinated with dTpa or diphtheria and tetanus toxoids followed by acellular pertussis (DT+ap) 1 month later in a clinical trial 10 years previously received 1 dTpa dose. Blood samples were taken before and 1 month after vaccination. Antibody concentrations against vaccine antigens were measured by enzyme-linked immunosorbent assay. Solicited and unsolicited symptoms and serious adverse events were recorded. RESULTS Eighty-two individuals were enrolled in the study. In the 75 individuals who had received the dTpa vaccine 10 years previously, prevaccination seroprotection or seropositivity rates were 98.8% (diphtheria), 97.5% (tetanus), 64.6% (pertussis toxoid), 100% (filamentous hemagglutinin), and 96.3% (pertactin). One month after the second booster, all study participants were seroprotected or seropositive against all vaccine antigens. Antibody concentrations increased by a similar magnitude as 10 years previously. During the 4-day follow-up, 9.9% of participants recorded grade 3 pain; 17.3% and 18.5% recorded redness and swelling of 50 mm or larger, respectively; and 8.6% recorded fever (temperature, 37.5 degrees C). No serious adverse events were considered causally related to the vaccine. CONCLUSIONS A second dTpa booster was highly immunogenic and well tolerated in this population of young adults. This study supports the use of this vaccine as a decennial booster. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00610168 .

Appearance of Bordetella pertussis strains not expressing the vaccine antigen pertactin in Finland.

Despite extensive vaccinations, resurgence of pertussis has been reported in many countries ([9][1]). Recently, emergence of Bordetella pertussis isolates not expressing the vaccine antigen pertactin (Prn) or pertussis toxin was described in France, where surveillance of the clinical isolates has

Bordetella pertussis Protein Pertactin Induces Type-Specific Antibodies: One Possible Explanation for the Emergence of Antigenic Variants?

Divergence has been found between Bordetella pertussis vaccine strains and circulating strains. Polymorphism in pertactin (Prn) is essentially limited to region 1, which is made up of repeats. Today, the 3 most prevalent Prn variants are Prn1-3. Vaccine strains produce Prn1, whereas Prn2 is the predominant type found in circulating strains. We investigated how variation in region 1 affects the production of human serum antibodies. Individuals infected by Prn2 strains had significantly fewer antibodies to Prn1 did than those infected by Prn3 strains and those immunized with a booster dose of acellular vaccines containing Prn1. Moreover, in contrast to vaccine recipients and subjects infected by Prn3 strains, individuals infected by Prn2 strains had hardly any antibodies specific to the variable region of Prn1. These results indicate that conformational changes have occurred in the variable region of Prn, which may offer a possible explanation for the emergence of Prn2 strains in certain countries.

Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma

Background: Respiratory infections are well known triggers of asthma exacerbations, but their role in stable adult asthma remains unclear. Methods: 103 asthmatics and 30 control subjects were enrolled in the study. Sputum was induced by inhalation of 3% NaCl solution. Oropharyngeal swab specimens were obtained from the posterior wall of the oropharynx. Respiratory specimens were analysed by RT-PCR for rhinovirus, enterovirus and respiratory syncytial virus and by PCR for adenovirus, Chlamydia pneumoniae, Mycoplasma pneumoniae and Bordetella pertussis. Results: Sputum samples from two of the 30 healthy controls (6.7%), five of 53 patients with mild asthma (9.4%), and eight of 50 with moderate asthma (16.0%) were positive for rhinovirus. Rhinovirus positive asthmatic subjects had more asthma symptoms and lower forced expiratory volume in 1 second (FEV1) (79% predicted) than rhinovirus negative cases (93.5% predicted; p = 0.020). Chlamydia pneumoniae PCR was positive in 11 healthy controls (36.6%), 11 mild asthmatics (20.8%), and 11 moderate asthmatics (22%), and PCR positive asthmatics had lower FEV1/FVC than negative cases (78.2% v 80.8%, p = 0.023). Bordetella pertussis PCR was positive in 30 cases: five healthy controls (16.7%), 15 mild asthmatics (28.3%), and 10 moderate asthmatics (20%). Bordetella pertussis positive individuals had lower FEV1/FVC (77.1% v 80.7%, p = 0.012) and more asthma symptoms than B pertussis negative cases. Conclusions: Rhinovirus, C pneumoniae, and B pertussis are found in the sputum or pharyngeal swab specimens of asthmatic subjects without concurrent symptoms of infection or asthma exacerbation, as well as in some healthy controls. Positivity is associated with lower lung function and more frequent asthma symptoms.

Bordetella pertussis strain variation and evolution postvaccination.

Bordetella pertussis is a Gram-negative bacterium that causes pertussis or whooping cough in humans. The incidence of pertussis has increased in young infants, adolescents and adults in many countries where the vaccination against pertussis has been used extensively. Marked changes have been found in the B. pertussis population and differences have been observed between vaccine strains and circulating isolates. Moreover, clonal expansion of certain B. pertussis strains has been associated with the recent epidemics of pertussis in several European countries. In this review, we present data on strain variation and evolution of B. pertussis in different vaccinated populations and summarize the common methods for typing of B. pertussis and their relative discriminatory power.

Nasopharyngeal bacterial colonization and gene polymorphisms of mannose-binding lectin and toll-like receptors 2 and 4 in infants.

Background Human nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants. Methodology/Principal Findings From August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002). Conclusions Our study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections.