Immunodominance in T cell responses elicited against different domains of detoxified pneumolysin PlyD1.

Detoxified pneumolysin, PlyD1, is a protein vaccine candidate that induces protection against infections with Streptococcus pneumoniae in mouse models. Despite extensive knowledge on antibody responses against PlyD1, limited information is available about PlyD1 induced T cell recognition. Here we interrogated epitope breadth and functional characteristics of the T cell response to PlyD1 in two mouse strains.

Development and Qualification of an Opsonophagocytic Killing Assay To Assess Immunogenicity of a Bioconjugated Escherichia coli Vaccine.

The global burden of disease caused by extraintestinal pathogenic (ExPEC) is increasing as the prevalence of multidrug-resistant strains rises. A multivalent ExPEC O-antigen bioconjugate vaccine could have a substantial impact in preventing bacteremia and urinary tract infections. Development of an ExPEC vaccine requires a readout to assess the functionality of antibodies.

A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity.

Background: Group B , an endotoxin-producing Gram-negative bacterium, causes the highest incidence of group B meningococcus (MenB) disease in the first year of life. The Bexsero vaccine is indicated in Europe from 8 weeks of age. Endotoxin components of outer membrane vesicles (OMVs) or soluble lipopolysaccharide (LPS) represent a potential source of inflammation and residual reactogenicity.

Immunogenicity and safety of a tetravalent E. coli O-antigen bioconjugate vaccine in animal models.

Background: Extra-intestinal pathogenic Escherichia coli (ExPEC) are major human pathogens; however, no protective vaccine is currently available. We assessed in animal models the immunogenicity and safety of a 4-valent E. coli conjugate vaccine (ExPEC-4V, serotypes O1, O2, O6 and O25 conjugated to Exotoxin A from Pseudomonas aeruginosa (EPA)) produced using a novel in vivo bioconjugation method.

Importance of (antibody-dependent) complement-mediated serum killing in protection against Bordetella pertussis.

Pertussis is a highly contagious respiratory disease that is caused by Bordetella pertussis. Despite being vaccine preventable, pertussis rates have been rising steadily over the last decades, even in areas with high vaccine uptake. Recently, experiments with infant baboons indicated that although vaccination with acellular pertussis vaccines prevented disease, no apparent effect was observed on infection and transmission.

The mouse intranasal challenge model for potency testing of whole-cell pertussis vaccines.

Introduction: A mouse intracerebral challenge model is used for potency testing of whole-cell pertussis (wP) vaccines. We investigated the use of a mouse nasopharyngeal challenge model, which better reflects the clinical features of pertussis disease, to differentiate between efficacy of wP vaccines.

Methods: Efficacy of three wP vaccines (Quinvaxem(®), Easyfive(®) and Pentavac(®)) was tested in the nasopharyngeal challenge model.

The history of pneumococcal conjugate vaccine development: dose selection.

Pneumococcal conjugate vaccines (PCVs) differ in polysaccharide (PS) dose, carrier protein and conjugation method. PCV development proceeded initially upon principles successfully proven in Haemophilus influenzae type b (Hib) conjugate vaccine development. However, the need to successfully incorporate multiple serotypes while minimizing the total PS dose and total carrier protein load saw some early vaccine candidates fail.

Levels and functionality of antibodies after pneumococcal conjugate vaccine in schedules with different timing of the booster dose.

The seven-valent pneumococcal conjugate vaccine (PCV7) has been introduced in most high-income countries, although with differences in age, timing and number of primary doses before 6 months of age and presence and timing of a booster vaccination. The objective was to determine and compare the IgG antibody levels and functionality of IgG responses (avidity and opsonophagocytoses) at 1 and 2 years of age following 2 primary doses with a booster at 11 or 24 months of age. Children received PCV7 at 2 and 4 months (2-dose group), or at 2, 4 and 11 months (2+1-dose group), or no PCV7 (controls) before 1 year of age.

Improved production process for native outer membrane vesicle vaccine against Neisseria meningitidis.

An improved detergent-free process has been developed to produce vaccine based on native outer membrane vesicles (NOMV) against Neisseria meningitidis serogroup B. Performance was evaluated with the NonaMen vaccine concept, which provides broad coverage based on nine distinct PorA antigens. Scalable aseptic equipment was implemented, replacing undesirable steps like ultracentrifugation, inactivation with phenol, and the use of preservatives.

Cost-effectiveness of vaccination against meningococcal B among Dutch infants: Crucial impact of changes in incidence.

Objective: Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands.

Preclinical safety and immunogenicity evaluation of a nonavalent PorA native outer membrane vesicle vaccine against serogroup B meningococcal disease.

Background: An improved nonavalent PorA native outer membrane vesicle vaccine was developed with intrinsic adjuvating activity due to presence of less-toxic (lpxL1) LPS. In the present study, the safety and immunogenicity of this next-generation NonaMen vaccine were evaluated following repeated vaccination in rabbits and mice.

Methods: A repeated-dose toxicology study was performed in rabbits.

Salivary immune responses to the 7-valent pneumococcal conjugate vaccine in the first 2 years of life.

Background: The CRM197-conjugated 7-valent pneumococcal vaccine (PCV7) is protective against vaccine serotype disease and nasopharyngeal carriage. Data on PCV7-induced mucosal antibodies in relation to systemic or natural anticapsular antibodies are scarce.

Methods: In a randomized controlled setting, children received PCV7 at age 2 and 4 months (2-dose group), at age 2, 4 and 11 months (2+1-dose group) or no PCV7 (control group).

Long-term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis.

Background: Shifts in pneumococcal serotypes following introduction of 7-valent pneumococcal conjugate vaccine (PCV-7) may alter the presence of other bacterial pathogens co-inhabiting the same nasopharyngeal niche.

Methodology/principal Findings: Nasopharyngeal prevalence rates of S. pneumoniae, S.

Nonclinical vaccine safety evaluation: advantages of continuous temperature monitoring using abdominally implanted data loggers.

Fever has been reported as the most common adverse event after vaccination in infants and children. For this reason it is important that, prior to clinical testing of a new vaccine, change in body temperature following vaccination is tested carefully in nonclinical animal studies. Since both the timing and the height of the temperature peak after vaccination may differ from vaccine to vaccine, it is important that the time point for body temperature measurement should be chosen on a case-by-case basis with sufficient knowledge of the specific vaccine.

Is a single dose of meningococcal serogroup C conjugate vaccine sufficient for protection? experience from the Netherlands.

Background: The first meningococcal serogroup C (MenC) conjugate vaccine was licensed in 1999 and introduced in the United Kingdom. Countries that have implemented the MenC vaccine since then in their national immunisation programmes use different schedules. Nevertheless, all involved countries seem to experience substantial declines in the incidence of MenC disease.

Lower immunoglobulin G antibody responses to pneumococcal conjugate vaccination at the age of 2 years after previous nasopharyngeal carriage of Streptococcus pneumoniae.

Objective: To determine whether nasopharyngeal pneumococcal carriage with serotypes 6B, 19F, or 23F interferes with immunoglobulin G (IgG) antibody responses to vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) at the age 24 months.

Study Design: Blood samples were collected before and after a PCV7 challenge vaccination at age 24 months from subsets of children participating in a randomized controlled trial. Children previously had received two doses of PCV7 at 2 and 4 months, two plus one doses of PCV7 at 2, 4, and 11 months, or no dosage until 24 months.

A cyclic undecamer peptide mimics a turn in folded Alzheimer amyloid β and elicits antibodies against oligomeric and fibrillar amyloid and plaques.

The 39- to 42-residue amyloid β (Aβ) peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD). Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Aβ immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Aβ, which might have a physiologically relevant function.

Carriage of Streptococcus pneumoniae 3 years after start of vaccination program, the Netherlands.

To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) program, we conducted a cross-sectional observational study on nasopharyngeal carriage of Streptococcus pneumoniae 3 years after implementation of the program in the Netherlands. We compared pneumococcal serotypes in 329 prebooster 11-month-old children, 330 fully vaccinated 24-month-old children, and 324 parents with age-matched pre-PCV7 (unvaccinated) controls (ages 12 and 24 months, n = 319 and n = 321, respectively) and 296 of their parents. PCV7 serotype prevalences before and after PCV7 implementation, respectively, were 38% and 8% among 11-month-old children, 36% and 4% among 24-month-old children, and 8% and 1% among parents.

The structure of Neisseria meningitidis lipid A determines outcome in experimental meningococcal disease.

Lipopolysaccharide (LPS), a major component of the meningococcal outer membrane, is sensed by the host through activation of Toll-like receptor 4 (TLR4). Recently, we demonstrated that a surprisingly large fraction of Neisseria meningitidis disease isolates are lipid A mutants, due to inactivating mutations in the lpxL1 gene. The lpxL1 mutants activate human TLR4 much less efficiently than wild-type bacteria, which may be advantageous by allowing them to escape from the innate immune system.

Hyperproliferation of B cells specific for a weakly immunogenic PorA in a meningococcal vaccine model.

Highly homologous meningococcal porin A (PorA) proteins induce protective humoral immunity against Neisseria meningitidis group B infection but with large and consistent differences in the levels of serum bactericidal activity achieved. We investigated whether a poor PorA-specific serological outcome is associated with a limited size of the specific B-cell subpopulation involved. The numbers of PorA-specific splenic plasma cells, bone marrow (BM) plasma cells, and splenic memory B cells were compared between mice that received priming and boosting with the weakly immunogenic PorA (P1.

Bioneedles as vaccine carriers.

Bioneedles are small hollow mini implants fabricated from biodegradable polymers which can be filled with antigen. Bioneedles can be used for vaccination without syringes and needles. Formulations have been prepared containing tetanus toxoid with and without aluminum phosphate.

Immunogenicity of a combination vaccine containing pneumococcal conjugates and meningococcal PorA OMVs.

The pre-clinical immunogenicity of a combination vaccine containing 13-valent pneumococcal conjugate (13vPnC) vaccine (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRM197) and nine-valent meningococcal B PorA vaccine (NonaMen; serosubtypes P1.7,16; P1.5-1,2-2; P1.

CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity.

Introduction: Chemokines are a superfamily of small peptides involved in leukocyte chemotaxis and in the induction of cytokines in a wide range of infectious diseases. Little is known about their role in meningococcal sepsis in children and their relationship with disease severity and outcome.

Methods: Monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP) 1alpha, growth-related gene product (GRO)-alpha and interleukin (IL)-8 were measured in 58 children with meningococcal sepsis or septic shock on admission and 24 hours thereafter.

Porin A-specific antibody avidity in patients who are convalescing from meningococcal B disease.

Porin A (PorA), which determines the serosubtype of Neisseria meningitidis, is the main antigen of a candidate vaccine against serogroup B meningococci, which has been shown to induce high-avidity antibodies in children. We characterized the immune response of children after convalescing from meningococcal infection with a serosubtype P1.7-2,4 strain.

Meningococcal serogroup B infections: a search for a broadly protective vaccine.

Meningococcal disease is mainly caused by serogroup B in many West European countries. Recently, a highly efficacious vaccine against infections caused by serogroup C has been introduced in the UK and The Netherlands. However, an effective vaccine against serogroup B has not yet become available.