Variability in Vaccine Response and Trajectory in Early Childhood and Association with Demographic Variables, Antibiotic Exposure and Infection Proneness.

Introduction: We sought to explore the variability of antibody responses to multiple vaccines during early life in individual children, assess the trajectory of each child longitudinally, determine the associations of demographic variables and antibiotic exposures with vaccine-induced immunity, and link vaccine responsiveness to infection proneness.

Methods: In 357 prospectively-recruited children, age six through 36 months, antibody levels to 13 routine vaccine antigens were measured in sera at multiple time points and normalized to their respective protective thresholds to categorize children into four groups: very low, low, normal, and high vaccine responder. Demographic variables and frequency of antibiotic exposure data were collected.

Modeling conjugate vaccine and natural induced antibody correlates of protection for pneumococcal colonization and acute otitis media infection in young children.

We measured anti-pneumococcal serotype 19A vaccine-induced antibodies in 160 children (611 sera) after introduction of 13-valent pneumococcal conjugate vaccine and naturally-induced antibodies in 59 children (185 sera) after colonization and acute otitis media (AOM) episodes caused by strains expressing serotype 19A. Correlate of protection (COP) models were constructed using results from multiple prospectively-collected observations in individual children. Generalized estimating equations followed by logistic-regression was used.

Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.

Background: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation.

Respiratory Infection- and Asthma-prone, Low Vaccine Responder Children Demonstrate Distinct Mononuclear Cell DNA Methylation Pathways.

Background: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunisations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation.

Pneumococci Isolated From Children in Community-Based Practice Differ From Isolates Identified by Population- and Laboratory-Based Invasive Disease Surveillance.

Background: Characterizing strains causing noninvasive and invasive pneumococcal disease (IPD) may inform the impact of new pneumococcal conjugate vaccines (PCVs).

Methods: During 2011-2019, among children aged 6-36 months, pneumococcal serotype distribution and antibiotic nonsusceptibility of nasopharyngeal and middle ear fluid (MEF) isolates collected at onset of acute otitis media (AOM) in Rochester, New York, were compared with IPD isolates from the Active Bacterial Core surveillance (ABCs) system across 10 US sites.

Results: From Rochester, 400 (nasopharyngeal) and 156 (MEF) pneumococcal isolates were collected from 259 children.

Variability of Vaccine Responsiveness in Young Children.

Background: Variability in vaccine responsiveness among young children is poorly understood.

Methods: Nasopharyngeal secretions were collected in the first weeks of life for measurement of cytokines/chemokines seeking a biomarker, and blood samples were collected at age 1 year to identify vaccine responsiveness status, defined as low vaccine responder (LVR), normal vaccine responder (NVR), and high vaccine responder (HVR), to test for vaccine antigen-induced immune memory and for antigen-presenting cell (APC) function.

Results: Significantly lower specific cytokine/chemokine levels as biosignatures, measurable in nasopharyngeal secretions at infant age 1-3 weeks, predicted LVR status compared to NVR and HVR children.

Naturally-induced serum antibody levels in children to pneumococcal polysaccharide 15B that correlate with protection from nasopharyngeal colonization but anti-serotype 15B antibody has low functional cross-reactivity with serotype 15C.

Background: Serotypes 15B and 15C have been added to new different pneumococcal-conjugate vaccines (PCV20 and V116, respectively). We determined a serum anti-15B antibody level that would be a correlate of protection (COP) against nasopharyngeal colonization and assessed functional cross-reactivity against serotype 15B and 15C in children following natural immunization.

Method: IgG-antibody to serotype 15B polysaccharide was measured by ELISA in 341 sera from 6 to 36 month old children collected before, at the time of, and after pneumococcal colonization caused by serotypes 15B and 15C.

Variability of vaccine responsiveness in early life.

Vaccinations in early life elicit variable antibody and cellular immune responses, sometimes leaving fully vaccinated children unprotected against life-threatening infectious diseases. Specific immune cell populations and immune networks may have a critical period of development and calibration in a window of opportunity occurring during the first 100 days of early life. Among the early life determinants of vaccine responses, this review will focus on modifiable factors involving development of the infant microbiota and metabolome: antibiotic exposure, breast versus formula feeding, and Caesarian section versus vaginal delivery of newborns.

Very early life microbiome and metabolome correlates with primary vaccination variability in children.

We show that simultaneous study of stool and nasopharyngeal microbiome reveals divergent timing and patterns of maturation, suggesting that local mucosal factors may influence microbiome composition in the gut and respiratory system. Antibiotic exposure in early life as occurs commonly, may have an adverse effect on vaccine responsiveness. Abundance of gut and/or nasopharyngeal bacteria with the machinery to produce lipopolysaccharide-a toll-like receptor 4 agonist-may positively affect future vaccine protection, potentially by acting as a natural adjuvant.

Expression conditions and characterization of a novelly constructed lipoprotein intended as a vaccine to prevent human Haemophilus influenzae infections.

Bacterial lipoproteins are structurally divided into two groups, based on their lipid moieties: diacylated (present in Gram-positive bacteria) and triacylated (present in some Gram-positive and most Gram-negative bacteria). Diacylated and triacylated lipid moieties differ by a single amide-linked fatty acid chain. Lipoproteins induce host innate immune responses by the mammalian Toll-like receptor 2 (TLR2).

Colonization, Density, and Antibiotic Resistance of Streptococcus pneumoniae, Haemophilus Influenzae, and Moraxella catarrhalis among PCV13-Vaccinated Infants in the First Six Months of Life in Rochester, New York: A Cohort Study.

Background: Streptococcus pneumoniae (Spn), Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat) nasopharyngeal colonization precedes disease pathogenesis and varies among settings and countries. We sought to assess colonization prevalence, density, Spn serotypes, and antibiotic resistance in children in the first 6 months of life in pediatric primary care settings.

Methods: Prospective cohort study in Rochester, NY during 2018-2020.

Acute otitis media pneumococcal disease burden and nasopharyngeal colonization in children due to serotypes included and not included in current and new pneumococcal conjugate vaccines.

Introduction: Despite the introduction of effective pneumococcal conjugate vaccines (PCV), Streptococcus pneumoniae remains a major cause of acute otitis media (AOM) worldwide. New, higher valency vaccines that offer broader serotype coverage have been recently developed and others are in development. However, given the capsular serotypes expressed by pneumococci causing AOM, it is unclear to what extent differing or higher valency PCVs will provide additional protection.

Haemophilus influenzae Protein D antibody suppression in a multi-component vaccine formulation.

Nontypeable Haemophilus influenzae (NTHi) has emerged as a dominant mucosal pathogen causing acute otitis media (AOM) in children, acute sinusitis in children and adults, and acute exacerbations of chronic bronchitis in adults. Consequently, there is an urgent need to develop a vaccine to protect against NTHi infection. A multi-component vaccine will be desirable to avoid emergence of strains expressing modified proteins allowing vaccine escape.

Pathogenesis of Streptococcus pneumoniae serotype 3 during natural colonization and infections among children and its IgG correlate of protection in a mouse model.

Current licensed pneumococcal conjugate vaccines (PCVs) are effective against pneumococcal diseases caused by the serotypes contained in the PCvs However; several studies evaluating pneumococcal colonization and acute otitis-media (AOM) prevention in young children vaccinated with PCV13, observed less effectiveness against serotype-3. One possible reason for less effectiveness may be release of the capsular polysaccharide (CPS) of serotype-3 (CPS-3) as an immune evasion mechanism. Here we evaluated free CPS-3 levels released from 6 clinical isolates from young children compared to WU2 strain and to serotype-19A CPS (CPS-19A) released in vitro when interacting with nasopharyngeal, middle-ear and lung cell-lines.

Vaccine target and carrier molecule nontypeable Haemophilus influenzae protein D dimerizes like the close Escherichia coli GlpQ homolog but unlike other known homolog dimers.

We have determined the 1.8 Å X-ray crystal structure of nonlipidated (i.e.

Antibiotic Use and Vaccine Antibody Levels.

Background: The majority of children are prescribed antibiotics in the first 2 years of life while vaccine-induced immunity develops. Researchers have suggested a negative association of antibiotic use with vaccine-induced immunity in adults, but data are lacking in children.

Methods: From 2006 to 2016, children aged 6 to 24 months were observed in a cohort study.

Lipidation of Antigens P6 and OMP26 Improves Immunogenicity and Protection against Nasopharyngeal Colonization and Ear Infection.

Nontypeable Haemophilus influenzae (NTHi) causes respiratory infections that lead to high morbidity and mortality worldwide, encouraging development of effective vaccines. To achieve a protective impact on nasopharyngeal (NP) colonization by NTHi, enhanced immunogenicity beyond that achievable with recombinant-protein antigens is likely to be necessary. Adding a lipid moiety to a recombinant protein would enhance immunogenicity through Toll-like receptor 2 signaling of antigen-presenting cells and Th17 cell response in the nasal-associated lymphoid tissue (NALT).

Interferon-γ promotes monocyte-mediated lung injury during influenza infection.

Influenza A virus (IAV) infection triggers an exuberant host response that promotes acute lung injury. However, the host response factors that promote the development of a pathologic inflammatory response to IAV remain incompletely understood. In this study, we identify an interferon-γ (IFN-γ)-regulated subset of monocytes, CCR2 monocytes, as a driver of lung damage during IAV infection.

Transition of Serotype 35B Pneumococci From Commensal to Prevalent Virulent Strain in Children.

In our community-based prospective cohort study in young children, we observed a significant increase in pneumococcal serotype 35B nasopharyngeal (NP) commensal colonization during the 2011-2014 timeframe, but these strains were not associated with disease. Beginning in 2015 and continuing through to the present, the serotype 35B virulence changed, and it became the dominant bacteria isolated and associated with pneumococcal acute otitis-media (AOM) in our cohort. We performed comparative analyses of 250 35B isolates obtained from 140 children collected between 2006 and 2019.

Nasopharyngeal microbiome composition associated with Streptococcus pneumoniae colonization suggests a protective role of Corynebacterium in young children.

Streptococcus pneumoniae (Spn) is a leading respiratory tract pathogen that colonizes the nasopharynx (NP) through adhesion to epithelial cells and immune evasion. Spn actively interacts with other microbiota in NP but the nature of these interactions are incompletely understood. Using 16S rRNA gene sequencing, we analyzed the microbiota composition in the NP of children with or without Spn colonization.

Dynamic changes in otopathogens colonizing the nasopharynx and causing acute otitis media in children after 13-valent (PCV13) pneumococcal conjugate vaccination during 2015-2019.

The otopathogens colonizing the nasopharynx (NP) and causing acute otitis media (AOM) have shown dynamic changes following introduction of pneumococcal conjugate vaccines. Five hundred eighty-nine children were prospectively enrolled, 2015-2019. Two thousand fifty-nine visits (1528 healthy, 393 AOM, and 138 AOM follow-up) were studied.

Pneumonia, Sinusitis, Influenza and Other Respiratory Illnesses in Acute Otitis Media-Prone Children.

Background: Recurrent acute otitis media in the first years of life can be explained by immune dysfunction. Consequently, it would be expected that otitis-prone (OP) children would be more susceptible to other infectious diseases, especially respiratory infections, since a component of the immune problem involves nasopharyngeal innate immunity.

Design: Cohort study with prospective identification of all physician-diagnosed, medically attended respiratory illness visits in children 6 months to 5 years of age to determine the incidence of pneumonia, acute sinusitis, influenza and other bacterial and viral infections among OP compared with non-OP (NOP) children.