Molecular pathogenesis of infections caused by Moraxella catarrhalis in children

Moraxella catarrhalis (M. catarrhalis) is a human-restricted commensal of the normal bacterial flora in the upper respiratory tract of children, and - during the previous two decades - has been recognised as a true human pathogen. M. catarrhalis is the third most common pathogen causing acute otitis media in children, which is the most common reason to visit a paediatrician during childhood. Acute otitis media thus causes a high clinical and economical burden. With the introduction of the conjugate pneumococcal vaccines the microbiomic pattern in the nasopharyngeal flora of children has changed, and the frequency of isolation of M. catarrhalis has increased. Compared to adults, children are more often colonised with M. catarrhalis. Over the last three decades there has been a dramatic increase in the acquisition of β-lactam resistance in M. catarrhalis. Today 95-100% of clinically isolated M. catarrhalis produce β-lactamase. It is thus desirable to reduce the burden of M. catarrhalis disease by developing a vaccine. There are several potential vaccine antigen candidates in different stages of development, but none of them has entered clinical trials at the present time.

Plant-based immunocontraceptive control of wildlife - "potentials, limitations, and possums"

Possums (Trichosurus vulpecula), originally introduced from Australia, are spread over 90% of New Zealand and cause major economic and environmental damage. Immunocontraception has been suggested as a humane means to control them. Marsupial-specific reproductive antigens expressed at high levels in edible transgenic plant tissue might provide a safe, effective, and cheap oral delivery bait for immuno-contraceptive control. As proof of concept, female possums vaccinated with immunocontraceptive antigens showed reduced fertility, and possums fed with potato-expressed heat labile toxin-B (LT-B) had mucosal and systemic immune responses to the antigen. This demonstrated that immunocontraception was effective in possums and that oral delivery in edible plant material might be possible. Nuclear transformation with reporter genes showed that transgenic carrot roots accumulate high levels of foreign protein in edible tissues, indicating their potential as a delivery vector. However, prior to attempts at large scale production, more effective immunocontraceptive antigen-adjuvant formulations are probably required before plant-based immunocontraception can become a major tool for immunocontraceptive control of overabundant vertebrate pests. (c) 2004 Elsevier Ltd. All rights reserved.

Seasonal influenza vaccine effectiveness in Portugal: results from the EuroEVA project 2015/16

The EuroEVA study aimed to estimate the 2015-16 end of season influenza vaccine effectiveness for all population and for the influenza vaccination target group. The presented results resulted from implementation of the study during 2015/2016 season.

Self-reported vaccination in the elderly : SABE Bogotá study, Colombia

Objectives: To determine the frequency of vaccination in older adults within the city of Bogotá and to estimate the association with sociodemographic and health factors. Methods: This is a secondary data analysis from the SABE-Bogotá Study, a cross-sectional population-based study that included a total of 2,000 persons aged 60 years. Weighted percentages for self-reported vaccination [influenza, pneumococcal, tetanus] were determined. The association between vaccination and covariates was evaluate by logistic regression models. Results: A total of 73.0% of respondents received influenza, 57.8% pneumococcal and 47.6% tetanus vaccine. Factors independently associated with vaccination included: 1- age (65-74 years had higher odds of receiving vaccinations, compared to 60-64 years; 2- socioeconomic status (SES) (higher SES had lower odds of having influenza and pneumococcal vaccines, compared to those with lower SES); 3- health insurance (those with contributive or subsidized health insurance had higher odds (between 3 and 5 times higher) of having vaccinations, compared to those with no insurance); 4- older adults with better functional status (greater Lawton scores) had increased odds for all vaccinations; 5- older adults with higher comorbidity had increased odds for influenza and pneumococcal vaccinations. Conclusion: Vaccination campaigns should be strengthened to increase vaccination coverage, especially in the group more reticent to vaccination or vulnerable to reach it such as the disable elder.

Invasive pneumococcal infections in Finland before routine use of conjugate vaccines : opportunities for prevention

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis and bacteremia worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for adults less than 65 years old with certain chronic medical conditions and for all elderly persons because of high rates of invasive pneumococcal infections (IPI) and increased risk of death. This study provides a comprehensive picture of the epidemiology of pneumococcal infections in Finland before the introduction of childhood pneumococcal conjugate vaccines, focusing on disease rates, risk factors, clinical outcome, and healthcare associated infections. This study was based on national, population-based laboratory surveillance for IPI. Information on all episodes of IPI was collected from the primary diagnostic laboratory. A case with IPI was defined as the isolation of S. pneumoniae from blood or cerebrospinal fluid during 1995-2002. Information on comorbidities and underlying conditions for IPI patients was obtained by linking the IPI surveillance database to other national, population-based health registries using each patient’s unique national identity code. In total, 4357 cases of IPI were identified. The overall annualized IPI incidence increased by 35% during the study period and was 10.6 per 100 000 population. The temporal increase in disease rates was associated with higher blood culturing rates over time. In working age adults, two-thirds of severe infections and one half of fatal cases occurred in persons with no recognized PPV23 indication. Persons with asthma were at increased risk for IPI and this new risk factor accounted for 5% of the overall disease burden. One tenth of pneumococcal bacteremias were healthcare-associated, and mortality among these patients was over twice as high as among patients with community-associated bacteremia. Most patients with nosocomial infections had underlying conditions for which PPV23 is recommended. The incidence of IPI in Finland has increased and the overall disease burden is higher than previously reported. The findings of this study underscore the urgent need for improved prevention efforts against pneumococcal infections in Finland through increased use of PPV23 in adult risk groups and introduction of childhood immunization with pneumococcal conjugate vaccine.

Differential antibody responses to Pneumococcal and Tetanus vaccines in asymptomatic HIV-infected patients :a serological and cellular study

info:eu-repo/semantics/nonPublished

Nasal immunization of mice with Lactobacillus casei expressing the Pneumococcal Surface Protein A: induction of antibodies, complement deposition and partial protection against Streptococcus pneumoniae challenge

Strategies for the development of new vaccines against Streptococcus pneumoniae infections try to overcome problems such as serotype coverage and high costs, present in currently available vaccines. Formulations based on protein candidates that can induce protection in animal models have been pointed as good alternatives. Among them, the Pneumococcal Surface Protein A (PspA) plays an important role during systemic infection at least in part through the inhibition of complement deposition on the pneumococcal surface, a mechanism of evasion from the immune system. Antigen delivery systems based on live recombinant lactic acid bacteria (LAB) represents a promising strategy for mucosal vaccination, since they are generally regarded as safe bacteria able to elicit both systemic and mucosal immune responses. In this work, the N-terminal region of clade I PspA was constitutively expressed in Lactobacillus casei and the recombinant bacteria was tested as a mucosal vaccine in mice. Nasal immunization with L. casei-PspA 1 induced anti-PspA antibodies that were able to bind to pneumococcal strains carrying both clade 1 and clade 2 PspAs and to induce complement deposition on the surface of the bacteria. In addition, an increase in survival of immunized mice after a systemic challenge with a virulent pneumococcal strain was observed. (C) 2008 Elsevier Masson SAS. All rights reserved.

Modeling the impact of potential vaccines on epidemics of sexually transmitted chlamydia trachomatis infection

Background. We investigated the likely impact of vaccines on the prevalence of and morbidity due to Chlamydia trachomatis (chlamydia) infections in heterosexual populations. Methods.An individual‐based mathematical model of chlamydia transmission was developed and linked to the infection course in chlamydia‐infected individuals. The model describes the impact of a vaccine through its effect on the chlamydial load required to infect susceptible individuals (the “critical load”), the load in infected individuals, and their subsequent infectiousness. The model was calibrated using behavioral, biological, and clinical data. Results.A fully protective chlamydia vaccine administered before sexual debut can theoretically eliminate chlamydia epidemics within 20 years. Partially effective vaccines can still greatly reduce the incidence of chlamydia infection. Vaccines should aim primarily to increase the critical load in susceptible individuals and secondarily to decrease the peak load and/or the duration of infection in vaccinated individuals who become infected. Vaccinating both sexes has a beneficial impact on chlamydia‐related morbidity, but targeting women is more effective than targeting men. Conclusions.Our findings can be used in laboratory settings to evaluate vaccine candidates in animal models, by regulatory bodies in the promotion of candidates for clinical trials, and by public health authorities in deciding on optimal intervention strategies.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis : protocol for a randomised controlled trial

Background Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children. Methods A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW(135)) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and >= 6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged >= 6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine-related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged >= 6 years; and vaccine safety. Discussion As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.

Antibodies mediate formation of neutrophil extracellular traps in the middle ear and facilitate secondary pneumococcal otitis media

Otitis media (OM) (a middle ear infection) is a common childhood illness that can leave some children with permanent hearing loss. OM can arise following infection with a variety of different pathogens, including a coinfection with influenza A virus (IAV) and Streptococcus pneumoniae (the pneumococcus). We and others have demonstrated that coinfection with IAV facilitates the replication of pneumococci in the middle ear. Specifically, we used a mouse model of OM to show that IAV facilitates the outgrowth of S. pneumoniae in the middle ear by inducing middle ear inflammation. Here, we seek to understand how the host inflammatory response facilitates bacterial outgrowth in the middle ear. Using B cell-deficient infant mice, we show that antibodies play a crucial role in facilitating pneumococcal replication. We subsequently show that this is due to antibody-dependent neutrophil extracellular trap (NET) formation in the middle ear, which, instead of clearing the infection, allows the bacteria to replicate. We further demonstrate the importance of these NETs as a potential therapeutic target through the transtympanic administration of a DNase, which effectively reduces the bacterial load in the middle ear. Taken together, these data provide novel insight into how pneumococci are able to replicate in the middle ear cavity and induce disease.

Using immunology and resistant sheep to beat the fly

New methods for controlling blowfly strike will be needed when mulesing is phased out and the availability or efficacy of insecticides for control of fly strike decreases. The Australian Sheep Industry CRC has pursued two approaches for the development of new methods to help control blowfly strike. In the first, genetic resistance of sheep to survival and growth of blowfly larvae was examined. Resistance to growth of larvae was heritable (0.29 ± 0.22). The trait was not associated with resistance to internal parasites, nor was it influenced by wool characteristics such as fibre diameter or coefficient of variation of fibre diameter. This new trait differs from resistance to fly strike associated with resistance to fleece rot. Because measurement of the trait is labour intensive, gene markers or correlated measures are needed before it will be suitable for industry adoption. The second approach examined the impact of larval products on the immmune system of the sheep. Larvae suppress the sheep immune system and thereby limit the ability of the sheep to reject the larvae. The immunosuppresive agent is being purified and strategies to abolish its activity are being explored. Abolition of immunosuppression would create opportunities for the development of new vaccines againts blowfly strike.

Interplay of Virulence Factors in Complement Resistance of Streptococcus pneumoniae

Streptococcus pneumoniae (pneumococcus) is a normal inhabitant of the human nasopharynx. Symptoms occur in only a small proportion of those who become carriers, but the ubiquity of the organism in the human population results in a large burden of disease. S. pneumoniae is the leading bacterial cause of pneumonia, sepsis, and meningitis worldwide, causing the death of a million children each year. Middle-ear infection is the most common clinical manifestation of mucosal pneumococcal infections. In invasive disease, S. pneumoniae gains access to the bloodstream and spreads to normally sterile parts of the body. The progression from asymptomatic colonization to disease depends on factors characteristic of specific pneumococcal strains as well as the status of host defenses. The polysaccharide capsule surrounding the bacterium is considered to be the most important factor affecting the virulence of pneumococci. It protects pneumococci from phagocytosis and also may determine its affinity to the respiratory epithelium. S. pneumoniae as a species comprises more than 90 different capsular serotypes, but not all of them are equally prevalent in human diseases. Invasive serotypes are rarely isolated from healthy carriers, but relatively often cause invasive disease. Serotypes that are carried asymptomatically for a long time behave like opportunistic pathogens, causing disease in patients who have impaired immune defenses. The complement system is a collection of blood and cell surface proteins that act as a major primary defense against invading microbes. Phagocytic cells with receptors for complement proteins can engulf and destroy pneumococcal cells opsonized with these proteins. S. pneumoniae has evolved a number of ways to subvert mechanisms of innate immunity, and this is likely to contribute to its pathogenicity. The capsular serotype, proteins essential for virulence, as well the genotype, may all influence the ability of pneumococcus to resist complement and its potential to cause disease. Immunization with conjugate vaccines produces opsonic antibodies, which enhance complement deposition and clearance of the bacteria. The pneumococcal vaccine included in the Finnish national immunization program in 2010 contains the most common serotypes causing invasive disease. Clinical data suggest that protection from middle-ear infection and possibly also from invasive disease depends largely on the capsular serotype, for reasons hitherto unknown. The general aim of this thesis is to assess the relative roles of the pneumococcal capsule and virulence proteins in complement evasion and subsequent opsonophagocytic killing. The main question is whether differences between serotypes to resist complement explain the different abilities of serotypes to cause disease. The importance of particular virulence factors to the complement resistance of a strain may vary depending on its genotype. Prior studies have evaluated the effect of the capsule and virulence proteins on complement resistance of S. pneumoniae by comparing only a few strains. In this thesis, the role of pneumococcal virulence factors in the complement resistance of the bacterium was studied in several genotypically different strains. The ability of pneumococci to inhibit deposition of the complement protein C3 on the bacterial surface was found to depend on the capsular serotype as well as on other features of the bacteria. The results suggest that pneumococcal histidine triad (Pht) proteins may play a role in complement inhibition, but their contribution depends on the bacterial genotype. The capsular serotype was found to influence complement resistance more than the bacterial genotype. A higher concentration of anticapsular antibodies was required for the opsonophagocytic killing of serotypes resistant to C3 deposition. The invasive serotypes were more resistant to C3 deposition than the opportunistic serotypes, suggesting that the former are better adapted to resist immune mechanisms controlling the development of invasive disease. The different susceptibilities of serotypes to complement deposition, opsonophagocytosis, and resultant antibody-mediated protection should be taken into account when guidelines for serological correlates for vaccine efficacy evaluations are made. The results of this thesis suggest that antibodies in higher quantity or quality are needed for efficient protection against the invasive serotypes.

Mother-Infant Antibodies to Pneumococcal Polysaccharides and Proteins : Transfer and Persistence of Maternal Antibodies and Development of Vaccine-Induced and Naturally Acquired Antibodies in Infants

Symptomless nasopharyngeal carriage of Streptococcus pneumoniae (pneumococcus) is very common in young children. Occasionally the carriage proceeds into mild mucosal diseases, such as sinusitis or acute otitis media, or into serious life-threatening diseases, such as pneumonia, sepsis or meningitis. Each year, up to one million children less than five years of age worldwide die of invasive pneumococcal diseases (IPD). Especially in the low-income countries IPD is a leading health problem in infants; 75% of all IPD cases occur before one year of age. This stresses the need of increased protection against pneumococcus in infancy. Anti-pneumococcal antibodies form an important component in the defence against pneumococcal infection. Maternal immunisation and early infant immunisation are two possible ways by which potentially protective antibody concentrations against pneumococci could be achieved in early infancy. The aim of this thesis is to increase the knowledge of antibody mediated protection against pneumococcal disease in infants and young children. We investigated the transfer of maternal anti-pneumococcal antibodies from Filipino mothers to their infants, the persistence of the transferred antibodies in the infants, the immunogenicity of the 23-valent pneumococcal polysaccharide vaccine (PPV) in infants and the response of the children to a second dose of PPV at three years of age. We also investigated the development of antibodies to pneumococcal protein antigens in relation to culture-confirmed pneumococcal carriage in infants. Serum samples were collected from the mothers, the umbilical cords and from the infants at young age as well as at three years of age. The samples were used to determine the antibody concentrations to pneumococcal serotypes 1, 5, 6B, 14, 18C and 19F, as well as to the pneumococcal proteins PspA, PsaA, Ply, PspC, PhtD, PhtDC and LytC by the enzyme immunoassay. The findings of the present study confirm previously obtained results and add to the global knowledge of responses to PPV in young children. Immunising pregnant women with PPV provides the infants with increased concentrations of pneumococcal polysaccharide antibodies. Of the six serotypes examined, serotypes 1 and 5 were immunogenic already in infants. At three years of age, the children responded well to the second dose of PPV suggesting that maternal and early infant immunisations might not induce hyporesponsiveness to polysaccharide antigens after subsequent immunisations. The anti-protein antibody findings provide useful information for the development of pneumococcal protein vaccines. All six proteins studied were immunogenic in infancy and the development of anti-protein antibodies started early in life in relation to pneumococcal carriage.