Immune responses in neonates.

Neonates have little immunological memory and a developing immune system, which increases their vulnerability to infectious agents. Recent advances in the understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequency of lymphocytes, antigenic dose and mode of exposure. Studies in neonatal mouse models and human umbilical cord blood cells demonstrate the capability of neonatal immune cells to produce immune responses similar to adults in some aspects but not others.

Contributions to protection from Streptococcus pneumoniae infection using the monovalent recombinant protein vaccine candidates PcpA, PhtD, and PlyD1 in an infant murine model during challenge.

A vaccine consisting of several conserved proteins with different functions directing the pathogenesis of pneumonia and sepsis would be preferred for protection against infection by Streptococcus pneumoniae. Infants will be the major population targeted for next-generation pneumococcal vaccines. Here, we investigated the potential efficacy provided by three recombinant pneumococcal vaccine candidate proteins--pneumococcal histidine triad D (PhtD), detoxified pneumolysin derivative (PlyD1), and pneumococcal choline-binding protein A (PcpA)--for reducing pneumonia and sepsis in an infant mouse vaccine model.

Challenges in vaccination of neonates, infants and young children.

All neonates, infants and young children receive multiple priming doses and booster vaccinations in the 1st and 2nd year of life to prevent infections by viral and bacterial pathogens. Despite high vaccine compliance, outbreaks of vaccine-preventable infections are occurring worldwide. These data strongly argue for an improved understanding of the immune responses of neonates, infants and young children to vaccine antigens and further study of the exploitable mechanisms to achieve more robust and prolonged immunity with fewer primary and booster vaccinations in the pediatric population.

Payment analysis of two diagnosis and management approaches of acute otitis media.

We determined the cost of care for 2 diagnosis and management approaches for acute otitis media (AOM) among children 6 to 30 months old. A case-control design was used. Cases included 208 children diagnosed with AOM based on a bulging tympanic membrane (TM) and treated with amoxicillin/clavulanate.

Differential impact of respiratory syncytial virus and parainfluenza virus on the frequency of acute otitis media is explained by lower adaptive and innate immune responses in otitis-prone children.

Background: Acute otitis media (AOM) is a leading cause of bacterial pediatric infections associated with viral upper respiratory infections (URIs). We examined the differential impact of respiratory syncytial virus (RSV) and parainfluenza virus URIs on the frequency of AOM caused by Streptococcus pneumoniae (Spn) and nontypeable Haemophilus influenzae (NTHi) in stringently defined otitis-prone (sOP) and non-otitis-prone (NOP) children as a potential mechanism to explain increased susceptibility to AOM.

Methods: Peripheral blood and nasal washes were obtained from sOP and NOP children (n = 309).

Vaccination with a Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model.

Streptococcus pneumoniae infections continue to cause significant worldwide morbidity and mortality despite the availability of efficacious serotype-dependent vaccines. The need to incorporate emergent strains expressing additional serotypes into pneumococcal polysaccharide conjugate vaccines has led to an identified need for a pneumococcal protein-based vaccine effective against a broad scope of serotypes. A vaccine consisting of several conserved proteins with different functions during pathogenesis would be preferred.

The ToxAvapA toxin-antitoxin locus contributes to the survival of nontypeable Haemophilus influenzae during infection.

Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that is a common cause of acute and recurrent mucosal infections. One uncharacterized NTHi toxin-antitoxin (TA) module, NTHI1912-1913, is a host inhibition of growth (higBA) homologue. We hypothesized that this locus, which we designated toxAvapA, contributed to NTHi survival during infection.

Five-year prospective study of paediatric acute otitis media in Rochester, NY: modelling analysis of the risk of pneumococcal colonization in the nasopharynx and infection.

During a 5-year prospective study of nasopharyngeal (NP) colonization and acute otitis media (AOM) infections in children during the 7-valent pneumococcal conjugate vaccine (PCV) era (July 2006-June 2011) we studied risk factors for NP colonization and AOM. NP samples were collected at ages 6, 9, 12, 15, 18, 24, and 30 months during well-child visits. Additionally, NP and middle ear fluid (MEF) samples were collected at onset of every AOM episode.

Effects of Experimental Sarcocystis neurona-Induced Infection on Immunity in an Equine Model.

Sarcocystis neurona is the most common cause of Equine Protozoal Myeloencephalitis (EPM), affecting 0.5-1% horses in the United States during their lifetimes. The objective of this study was to evaluate the equine immune responses in an experimentally induced Sarcocystis neurona infection model.

Ultrasound imaging and characterization of biofilms based on wavelet de-noised radiofrequency data.

The ability to non-invasively image and characterize bacterial biofilms in children during nasopharyngeal colonization with potential otopathogens and during acute otitis media would represent a significant advance. We sought to determine if quantitative high-frequency ultrasound techniques could be used to achieve that goal. Systematic time studies of bacterial biofilm formation were performed on three preparations of an isolated Haemophilus influenzae (NTHi) strain, a Streptococcus pneumoniae (Sp) strain and a combination of H.

Co-colonization by Haemophilus influenzae with Streptococcus pneumoniae enhances pneumococcal-specific antibody response in young children.

Background: Streptococcus pneumoniae (Spn), Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mcat) are common bacterial pathogens of respiratory infections and common commensal microbes in the human nasopharynx (NP). The effect of interactions among theses bacteria during co-colonization of the NP on the host immune response has not been evaluated. The objective of this study was to assess the impact of co-colonization by Hi or Mcat on the systemic antibody response to vaccine protein candidate antigens of Spn and similarly the impact of co-colonization by Spn and Mcat on antibody responses to Hi vaccine protein candidate antigens.

Protein carriers of conjugate vaccines: characteristics, development, and clinical trials.

The immunogenicity of polysaccharides as human vaccines was enhanced by coupling to protein carriers. Conjugation transformed the T cell-independent polysaccharide vaccines of the past to T cell-dependent antigenic vaccines that were much more immunogenic and launched a renaissance in vaccinology. This review discusses the conjugate vaccines for prevention of infections caused by Hemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis.

CD4 T cell memory and antibody responses directed against the pneumococcal histidine triad proteins PhtD and PhtE following nasopharyngeal colonization and immunization and their role in protection against pneumococcal colonization in mice.

The present study was undertaken to understand the role of vaccine candidates PhtD and PhtE in pneumococcal nasopharyngeal (NP) colonization, their ability to induce CD4 T cell memory and antibody responses following primary NP colonization, and their contribution to protection against secondary pneumococcal colonization in mice. The study was also aimed at understanding the potential of immunization with PhtD and PhtE in eliciting qualitative CD4 T cell memory responses and protection against pneumococcal NP colonization in mice. PhtD and PhtE isogenic mutants in a TIGR4 background (TIGR4 ΔPhtD and TIGR4 ΔPhtE) were constructed and found to have a significantly reduced colonization density over time in the nasopharynges of mice compared to those of mice colonized with wild-type TIGR4.

Acute otitis media otopathogens during 2008 to 2010 in Rochester, New York.

Background: The otopathogen distribution colonizing the nasopharynx (NP) and causing acute otitis media (AOM) is in flux following the introduction of pneumococcal conjugate vaccine 7 (PCV7) and will continue to change.

Methods: Two hundred seventy-seven children were followed prospectively; tympanocentesis was performed during AOM and 208 NP samples were collected to compare with middle ear fluid (MEF) isolates. Eight hundred sixty-three NP samples were collected at 7 healthy visits between 6 and 30 months of age.

Relationship with original pathogen in recurrence of acute otitis media after completion of amoxicillin/clavulanate: bacterial relapse or new pathogen.

Objective: We sought to determine whether recurrent acute otitis media (rAOM) occurring within 30 days of amoxicillin/clavulanate treatment was caused by bacterial relapse or new pathogens.

Methods: Pneumococcal conjugate vaccinated children, age 6-36 months, enrolled in a prospective, longitudinal study experiencing rAOM<1 month after completing amoxicillin/clavulanate therapy were studied. AOM episodes occurred between June 2006 and November 2012.

Lower nasopharyngeal epithelial cell repair and diminished innate inflammation responses contribute to the onset of acute otitis media in otitis-prone children.

About 30 % of young children experience excessive, frequent episodes of middle ear infection and are classified as acute otitis media prone (OP). Streptococcus pneumoniae (Spn) is a predominant otopathogen in OP and non-OP (NOP) children. The pathogenesis of middle ear infection involves otopathogen nasopharyngeal (NP) colonization followed by an upper respiratory viral infection that modifies the NP environment to allow a sufficient inoculum of bacteria to reflux via the Eustachian tube into the middle ear space.

Otitis media.

Acute otitis media (AOM) is diagnosed based on visualization of a full or bulging tympanic membrane with middle ear effusion. The distribution of bacteria causing AOM in North America under the influence of pneumococcal conjugate vaccination and antibiotic selection pressure has resulted in a predominance of β-lactamase-producing Haemophilus influenzae followed by penicillin-resistant Streptococcus pneumoniae. Although guidelines continue to endorse amoxicillin as the preferred treatment, amoxicillin/clavulanate in high dosage would be the preferred treatment based on the otopathogen mix currently.

Deficiencies in the CD4 T-Helper Cell Arm of the Immune System of Neonates and Young Children.

Newborns and young children rely on innate immunity to protect against infections until the adaptive immune system matures. Immunization helps facilitate protection, but multiple doses are needed to establish sufficient antibody levels and T-cell-facilitated immune memory. Deficient T-cell activation and function among neonates and young children are primarily present in the CD4 compartment, whereas CD8 T-cell function is at par with adults.

Transcriptome signature in young children with acute otitis media due to non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in young children. In our recent paper in Microbes and Infection we described the transcriptome signature elicited from PBMCs at onset of AOM caused by Streptococcus pneumoniae. In the current study we found very different results with NTHi AOM infections; 5.

Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by Streptococcus pneumoniae compared to Haemophilus influenzae and Moraxella catarrhalis.

Objectives/hypothesis: Acute otitis media (AOM) involves an inflammatory response to microbes in the middle ear that facilitates clearance of otopathogens. Clinically, Streptococcus pneumoniae (Spn) infections of the respiratory tract are characterized by greater inflammatory responses than nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat). Interleukin 10 (IL-10) plays an important role in down-regulating the inflammatory response.

Reducing the frequency of acute otitis media by individualized care.

Objective: We sought to determine if use of more stringent diagnostic criteria for acute otitis media (AOM) than currently advocated by the American Academy of Pediatrics, tympanocentesis and pathogen-specific antibiotic treatment (individualized care) would result in reducing the incidence of recurrent AOM and consequent tympanostomy tube surgery.

Methods: A 5-year longitudinal, prospective study in Rochester, NY, was conducted from July 2006 to July 2011 involving 254 individualized care children. When this individualized care group developed symptoms of AOM, strict diagnostic criteria were applied and a tympanocentesis was performed.

Impact of respiratory viral infections on α-hemolytic streptococci and otopathogens in the nasopharynx of young children.

Background: We studied nasopharyngeal (NP) colonization in a cohort of children to determine the impact of viral upper respiratory infections (URIs) on nonpneumococcal α-hemolytic streptococci (AHS) and otopathogen colonization in association with acute otitis media (AOM).

Methods: NP samples were collected routinely when children were aged 6, 9, 12, 15, 18, 24 and 30 months and during episodes of AOM. NP samples were prospectively obtained from 248 children during a 5-year time span: 1018 during routine visits, 161 at the time of AOM and 59 at follow-up visits 3 weeks after AOM.

Multiple distinct forms of CD8+ T cell cross-reactivity and specificities revealed after 2009 H1N1 influenza A virus infection in mice.

Influenza primed mice are protected against lethal infection with H1N1 A/CA/04/E3/09 virus, and T depletion and serum transfer studies suggest a T-dependent mechanism. We therefore set out to investigate the quality of the cross-reactive T cell response to CA/E3/09 in mice primed with H3N2 influenza A/Hong Kong/X31 virus. Sequences of the immunodominant nucleoprotein (NP) NP366-374 and acid polymerase (PA) PA224-233 CD8 epitopes from X31 each differ from the CA/E3/09 virus by one amino acid: an M371V substitution at position 6 of the NP peptide, and an S224P substitution at position 1 of the PA peptide, raising questions about the role of these epitopes in protection.