How has post-implementation surveillance of high-coverage vaccination with HPV16/18-AS04 vaccine in England added to evidence about its cross-protective effects?

Background: Bivalent human papillomavirus HPV16/18-AS04 vaccine (Cervarix, GSK) offers direct protection against HPV16/18. Results from randomised controlled trials showed cross protective effects and suggested that declines in some closely related HPV types could be expected in a population with high vaccination coverage.

Aim: To evaluate the evidence for cross-protection afforded by HPV16/18-AS04 from post-implementation surveillance in England, and how this complements clinical trial data and post-implementation observations in other countries.

Cytokine Biomarkers of Exacerbations in Sputum From Patients With Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study.

Background: We determined the relationships between cytokine expression in sputum and clinical data to characterize and understand chronic obstructive pulmonary disease (COPD) exacerbations in people with COPD.

Methods: We measured 30 cytokines in 936 sputum samples, collected at stable state and exacerbation visits from 99 participants in the Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) study (ClinicalTrials.gov NCT01360398).

Ex-vivo RNA expression analysis of vaccine candidate genes in COPD sputum samples.

Background: Chronic obstructive pulmonary disease (COPD) is a lung disease characterised by airflow-limiting inflammation and mucus production. Acute exacerbations are a major cause of COPD-related morbidity and mortality and are mostly associated with bacterial or viral infections. A vaccine targeting non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat), the main bacteria associated with exacerbations, was tested in a Phase 2 trial.

Impact of bacterial strain acquisition in the lung of patients with COPD: the AERIS study.

Background: Bacterial infections are associated with acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but the mechanism is incompletely understood.

Method: In a COPD observational study (NCT01360398), sputum samples were collected monthly at the stable state and exacerbation. analyses of 1307 non-typeable (NTHi) isolates from 20 patients and 756 isolates from 38 patients in one year of follow-up were conducted by multilocus sequence typing (MLST).

UspA2 is a cross-protective Moraxella catarrhalis vaccine antigen.

Moraxella catarrhalis (Mcat) is a key pathogen associated with exacerbations of chronic obstructive pulmonary disease (COPD) in adults and playing a significant role in otitis media in children. A vaccine would help to reduce the morbidity and mortality associated with these diseases. UspA2 is an Mcat surface antigen considered earlier as vaccine candidate before the interest in this molecule vanished due to sequence variability.

A Protein E-PilA Fusion Protein Shows Vaccine Potential against Nontypeable Haemophilus influenzae in Mice and Chinchillas.

PE-PilA is a fusion protein composed of immunologically relevant parts of protein E (PE) and the majority subunit of the type IV pilus (PilA), two major antigens of nontypeable (NTHi). Here we report on the preclinical evaluation of PE-PilA as a vaccine antigen. The immunogenic potential of the PE and PilA within the fusion was compared with that of isolated PE and PilA antigens.

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations.

Background: Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD.

Objective: To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes.

Methods: We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene.

Interleukin-22 protects against non-typeable Haemophilus influenzae infection: alteration during chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is a major health problem becoming a leading cause of morbidity and mortality worldwide. A large part of these disorders is associated with acute exacerbations resulting from infection by bacteria, such as non-typeable Haemophilus influenzae (NTHi). Our understanding of the pathogenesis of these exacerbations is still elusive.

Recombinant protein truncation strategy for inducing bactericidal antibodies to the macrophage infectivity potentiator protein of Neisseria meningitidis and circumventing potential cross-reactivity with human FK506-binding proteins.

A recombinant macrophage infectivity potentiator (rMIP) protein of Neisseria meningitidis induces significant serum bactericidal antibody production in mice and is a candidate meningococcal vaccine antigen. However, bioinformatics analysis of MIP showed some amino acid sequence similarity to human FK506-binding proteins (FKBPs) in residues 166 to 252 located in the globular domain of the protein. To circumvent the potential concern over generating antibodies that could recognize human proteins, we immunized mice with recombinant truncated type I rMIP proteins that lacked the globular domain and the signal leader peptide (LP) signal sequence (amino acids 1 to 22) and contained the His purification tag at either the N or C terminus (C-term).

Immuno-proteomic analysis of human immune responses to experimental Neisseria meningitidis outer membrane vesicle vaccines identifies potential cross-reactive antigens.

Human volunteers were vaccinated with experimental Neisseria meningitidis serogroup B vaccines based on strain H44/76 detoxified L3 lipooligosaccharide (LOS)-derived outer membrane vesicles (OMV) or the licensed Cuban vaccine, VA-MENGOC-BC. Some volunteers were able to elicit cross-bactericidal antibodies against heterologous L2-LOS strain (760676). An immuno-proteomic approach was used to identify potential targets of these cross-bactericidal antibodies using an L2-LOS derived OMV preparation.

Evaluation of truncated NhhA protein as a candidate meningococcal vaccine antigen.

NhhA (Neisseria hia homologue) is an outer membrane protein from Neisseria meningitidis, the causative agent of meningococcal disease. The protein is surface exposed and its expression in a wide range of meningococcal strains suggests it is a promising vaccine candidate. In addition, immunization of mice with outer membrane vesicles of strains that overexpress NhhA in conjunction with one of TbpA, Omp85 or NspA results in synergistic bactericidal responses.

Meningococcal omp85 in detergent-extracted outer membrane vesicle vaccines induces high levels of non-functional antibodies in mice.

The vaccine potential of meningococcal Omp85 was studied by comparing the immune responses of genetically modified deoxycholate-extracted outer membrane vesicles, expressing five-fold higher levels of Omp85, with wild-type vesicles. Groups (n = 6-12) of inbred and outbred mouse strains (Balb/c, C57BL/6, OFI and NMRI) were immunized with the two vaccines, and the induced antibody levels and bactericidal and opsonic activities measured. Except for Balb/c mice, which were low responders, the genetically modified vaccine raised high Omp85 antibody levels in all mouse strains.

ZnuD, a potential candidate for a simple and universal Neisseria meningitidis vaccine.

Neisseria meningitidis serogroup B (MenB) is a major cause of bacterial sepsis and meningitis, with the highest disease burden in young children. Available vaccines are based on outer membrane vesicles (OMVs) obtained from wild-type strains. However, particularly in toddlers and infants, they confer protection mostly against strains expressing the homologous protein PorA, a major and variable outer membrane protein.

Neisseria meningitidis serogroup B lipooligosaccharide genotyping reveals high prevalence of L2 strains in Spain and unexpected relationship with factor H-binding protein expression.

Neisseria meningitidis may be classified according to the lipooligosaccharide immunotype. We show that this classification can be achieved by PCR genotyping of the genes involved in the lipooligosaccharide inner-core biosynthesis, lpt3, lpt6, lgtG and lot3. Genotyping data correlated well (90-100%) with mass spectrometry data and was, therefore, applied to screen a random subset of recent N.

Measurement of functional anti-meningococcal serogroup a activity using strain 3125 as the target strain for serum bactericidal assay.

Functional anti-N. meningitidis serogroup A (MenA) activity in human serum is detected by serum bactericidal assay (SBA), using either rabbit (rSBA) or human (hSBA) complement, with F8238 as the recommended MenA SBA target strain. However, the F8238 strain may not be optimal for this purpose because, as we show here, it expresses the L11 immunotype, whereas most MenA invasive strains express the L(3,7)9 or L10 immunotype.

Three doses of an experimental detoxified L3-derived lipooligosaccharide meningococcal vaccine offer good safety but low immunogenicity in healthy young adults.

This open, randomized phase I study evaluated the safety and reactogenicity of an experimental meningococcal serogroup B (MenB) vaccine obtained from outer membrane vesicle detoxified L3-derived lipooligosaccharide. Healthy young adults (n = 150) were randomized to receive either experimental vaccine (provided in five formulations, n = 25 in each group) or VA-Mengoc-BC (control, n = 25) administered on a 0- to 6-week/6-month schedule. Serum bactericidal assays performed against three MenB wild-type strains assessed the immune response, defined as a 4-fold increase from pre- to postvaccination.

An outer membrane receptor of Neisseria meningitidis involved in zinc acquisition with vaccine potential.

Since the concentration of free iron in the human host is low, efficient iron-acquisition mechanisms constitute important virulence factors for pathogenic bacteria. In Gram-negative bacteria, TonB-dependent outer membrane receptors are implicated in iron acquisition. It is far less clear how other metals that are also scarce in the human host are transported across the bacterial outer membrane.

Genetically modified L3,7 and L2 lipooligosaccharides from Neisseria meningitidis serogroup B confer a broad cross-bactericidal response.

Currently available Neisseria meningitidis serogroup B (MenB) vaccines are based on outer membrane vesicles (OMVs) that are obtained from wild-type strains. They are purified with the aim of decreasing the lipooligosaccharide (LOS) content and hence reduce the reactogenicity of the vaccine even though LOS is a potential protective antigen. In <2-year-old children, these MenB vaccines confer protection only against strains expressing homologous PorA, a major and variable outer membrane protein.

Comparison of phenotypically indistinguishable but geographically distinct Neisseria meningitidis Group B isolates in a serum bactericidal antibody assay.

The "gold standard" assay for measuring serologic protection against Neisseria meningitidis group B (MenB) is the serum bactericidal antibody (SBA) assay. Of vital importance to the outcome of the SBA assay is the choice of the target strain(s), which is often chosen on the basis of phenotype or genotype. We therefore investigated the effect on the results produced by the SBA assay of using phenotypically indistinguishable but geographically distinct MenB isolates.

Additive and synergistic bactericidal activity of antibodies directed against minor outer membrane proteins of Neisseria meningitidis.

Neisseria meningitidis serogroup B is a major cause of bacterial meningitis in younger populations. The available vaccines are based on outer membrane vesicles obtained from wild-type strains. In children less than 2 years old they confer protection only against strains expressing homologous PorA, a major, variable outer membrane protein (OMP).

Immunogenicity and safety of three doses of a bivalent (B:4:p1.19,15 and B:4:p1.7-2,4) meningococcal outer membrane vesicle vaccine in healthy adolescents.

An experimental bivalent meningococcal outer membrane vesicle (OMV) vaccine (B:4:P1.19,15 and B:4:P1.7-2,4) has been developed to provide wide vaccine coverage particularly of the circulating strains in Europe.

Shielding of immunogenic domains in Neisseria meningitidis FrpB (FetA) by the major variable region.

The meningococcal iron-limitation-inducible outer membrane protein FrpB (FetA) has been shown to induce bactericidal antibodies, and is, therefore, considered a vaccine candidate. However, these antibodies are strain specific and, consistently, epitope mapping showed that they are directed against a region, located in a surface-exposed loop, L5, that displays considerable sequence variability between strains. Here, we attempted to redirect the immune response to more conserved domains of the protein by deleting L5.

Immunogenicity and structural characterisation of an in vitro folded meningococcal siderophore receptor (FrpB, FetA).

The iron-limitation-inducible protein FrpB of Neisseria meningitidis is an outer-membrane-localized siderophore receptor. Because of its abundance and its capacity to elicit bactericidal antibodies, it is considered a vaccine candidate. Bactericidal antibodies against FrpB are, however, type-specific.

Vaccine potential of the Neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB.

The vaccine potential of the Neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB was evaluated. Sequencing and sequence alignments suggested that LbpA is relatively well conserved with variability largely restricted to two surface-exposed loops in a proposed topology model. Consistently, antisera raised against synthetic peptides corresponding to exposed loops generally recognized the LbpA proteins of many different strains.