Genetic Correlates of Biological Aging and the Influence on Prediction of Mortality.

Longevity and disease-free survival are influenced by a combination of genetics and lifestyle. Biological age (BioAge), a measure of aging based on composite biomarkers, may outperform chronological age in predicting health and longevity. This study investigated the relationship between genetic risks, lifestyle factors, and delta age (Δage), estimated as the difference between biological and chronological age. BioAge and Δage were calculated for 52 418 participants from the population-based Lifelines cohort. We computed 2 independent polygenic risk scores (PRS) for health span and DNA methylation-based aging clock to characterize genetic risks. The capacity of BioAge to predict all-cause mortality when adjusted for chronological age and genetic risks for aging, was assessed. Obesity, lifestyle, socioeconomic status, sex, and genetic variations in a population contributed to the differences in the rates of accelerated aging. The overall risk of death for a 1-year increase in BioAge for a given chronological age and sex among the genotyped participants was 11% (HR = 1.11; 95% CI: 1.09, 1.13). After adjusting for genetic factors, BioAge maintained its sensitivity for predicting mortality. Findings from this study ascertain that BioAge can be a useful tool for risk stratification in research and aging interventions.

Pneumococcal carriage, serotype distribution, and antimicrobial susceptibility in Papua New Guinean children vaccinated with PCV10 or PCV13 in a head-to-head trial.

BACKGROUND: Children in Papua New Guinea (PNG) are at high risk of pneumococcal infections. We investigated pneumococcal carriage rates, serotype distribution, and antimicrobial susceptibility in PNG children after vaccination with 10-valent or 13-valent pneumococcal conjugate vaccines (PCV10; PCV13). METHODS: Infants (N = 262) were randomized to receive 3 doses of PCV10 or PCV13 at 1-2-3 months of age, followed by pneumococcal polysaccharide vaccination (PPV) or no PPV at 9 months of age. Nasopharyngeal swabs (NPS) collected at ages 1, 4, 9, 10, 23 and 24 months were cultured using standard bacteriological procedures. Morphologically distinct Streptococcus pneumoniae colonies were serotyped by the Quellung reaction. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion and minimum inhibitory concentration (MIC). RESULTS: S. pneumoniae was isolated from 883/1063 NPS collected at 1-23 months of age, including 820 serotypeable (64 different serotypes) and 144 non-serotypeable isolates. At age 23 months, 93.6% (95%CI 86.6-97.6%) of PCV10 recipients and 88.6% (95%CI 80.1-94.4%) of PCV13 recipients were pneumococcal carriers, with higher carriage of PCV10 serotypes by PCV10 recipients (19.8%, 95%CI 12.2-29.5) than PCV13 recipients (9.3%, 95%CI 4.1-17.3) (p = 0.049). There were no other statistically significant differences between PCV10 and PCV13 recipients and children receiving PPV or no PPV. Nearly half (45.6%) of carried pneumococci were non-susceptible to penicillin based on the meningitis breakpoint (MIC ≥ 0.12 µg/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC ≥ 8 µg/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19-2/38 µg/mL) and 16.9% full resistance (MIC ≥ 4/76 µg/mL). PCV serotypes 14 and 19A were commonly non-susceptible to both penicillin (14, 97%; 19A, 70%) and SXT (14, 97%; 19A, 87%). CONCLUSION: Even after PCV10 or PCV13 vaccination, children living in a high-risk setting such as PNG continue to experience high levels of pneumococcal colonization, including carriage of highly antimicrobial-resistant PCV serotypes. The study is registered with ClinicalTrials.gov (CTN NCT01619462).

A phase 2 randomized controlled dose-ranging trial of recombinant pertussis booster vaccines containing genetically inactivated pertussis toxin in women of childbearing age.

BACKGROUND: A phase 2 randomized-controlled safety and immunogenicity trial evaluating different doses of recombinant acellular pertussis vaccine containing genetically-inactivated pertussis toxin (PTgen) was conducted in women of childbearing age in Thailand to identify formulations to advance to a trial in pregnant women. METHODS: A total of 250 women were randomized 1:1:1:1:1 to receive one dose of one of three investigational vaccines including low-dose recombinant pertussis-only vaccine containing 1 µg PTgen and 1 µg FHA (ap1gen), tetanus, reduced-dose diphtheria (Td) combined to ap1gen (Tdap1gen) or combined to recombinant pertussis containing 2 µg PTgen and 5 µg FHA (Tdap2gen), or one dose of licensed recombinant TdaP vaccine containing 5 µg PTgen and 5 µg FHA (Boostagen®, TdaP5gen) or licensed Tdap vaccine containing 8 µg of chemically inactivated pertussis toxoid (PTchem), 8 µg FHA, and 2.5 µg pertactin (PRN) (BoostrixTM, Tdap8chem). Serum Immunoglobulin G (IgG) antibodies against vaccine antigens were measured before and 28 days after vaccination by ELISA. To advance to a trial in pregnant women, formulations had to induce a PT-IgG seroresponse rate with a 95% confidence interval (95% CI) lower limit of ≥ 50%. RESULTS: Between 5 and 22 July 2018, a total of 250 women with median age of 31 years were enrolled. Post-vaccination PT-IgG seroresponse rates were 92% (95% CI 81-98) for ap1gen, 88% (95% CI 76-95) for Tdap1gen, 80% (95% CI 66-90) for Tdap2gen, 94% (95% CI 83-99) for TdaP5gen, and 78% (95% CI 64-88) for Tdap8chem. Frequencies of injection site and systemic reactions were comparable between the groups. No serious adverse events were reported during the 28-day post-vaccination period. CONCLUSIONS: All recombinant acellular pertussis vaccines were safe and immunogenic in women of childbearing age, and all met pre-defined immunogenicity criteria to advance to a trial in pregnant women. CLINICAL TRIAL REGISTRATION: Thai Clinical Trial Registry, TCTR20180321004.

Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life.

Background: Development of vaccines to prevent disease and death from Streptococcus pneumoniae, and nontypeable Haemophilus influenzae (NTHi), the main pathogens that cause otitis media, pneumonia, meningitis and sepsis, are a global priority. Children living in low and lower-middle income settings are at the highest risk of contracting and dying from these diseases. Improved vaccines with broader coverage are required. Data on the natural development of antibodies to putative vaccine antigens, especially in high-risk settings, can inform the rational selection of the best antigens for vaccine development. Methods: Serum IgG titres to four pneumococcal proteins (PspA1, PspA2, CbpA, and Ply) and five NTHi antigens (P4, P6, OMP26, rsPilA and ChimV4) were measured in sera collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age using multiplexed bead-based immunoassays. Carriage density of S. pneumoniae and H. influenzae were assessed by quantitative PCR on genomic DNA extracted from nasopharyngeal swabs using species-specific primers and probes. All data were log-transformed for analysis using Student's unpaired t-tests with geometric mean titre (GMT) or density (GMD) calculated with 95% confidence intervals (CI). Results: Serum -pneumococcal protein-specific IgG titres followed a "U" shaped pattern, with a decrease in presumably maternally-derived IgG titres between 1 and 4 months of age and returning to similar levels as those measured at 1 month of age by 24 months of age. In contrast, NTHi protein-specific IgG titres steadily increased with age. There was no correlation between antibody titres and carriage density for either pathogen. Conclusion: This longitudinal study indicates that the waning of maternally- derived antibodies that is usually observed in infants, after infants does not occur for NTHi antigens in Papua New Guinean infants. Whether NTHi antigen IgG can be transferred maternally remains to be determined. Vaccines that are designed to specifically increase the presence of protective NTHi antibodies in the first few months of life may be most effective in reducing NTHi disease. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT01619462.

Antibody persistence 2 and 3 years after booster vaccination of adolescents with recombinant acellular pertussis monovalent aPgen or combined TdaPgen vaccines.

BACKGROUND: Recombinant pertussis vaccines inducing long-lasting immune responses could help to control the rise in pertussis. We here report on persisting antibody responses 2 and 3 years after booster vaccination with a new generation recombinant acellular pertussis vaccine. METHODS: Participants of a phase 2/3 randomised-controlled clinical trial with a monovalent pertussis vaccine containing genetically inactivated pertussis toxin (aPgen) or its tetanus and diphtheria toxoids combination (TdaPgen), or a chemically detoxified comparator vaccine (Tdapchem), (originally conducted between July and August 2015) were invited to participate in observational studies of persisting antibody responses 2 and 3 years after vaccination. Serum IgG against pertussis toxin (PT-IgG) and filamentous hemagglutinin (FHA-IgG) were assessed by ELISA, and PT-neutralising antibodies (PT-Nab) by Chinese Hamster Ovary cell assay. FINDINGS: Waning of antibodies stabilised in aPgen and TdaPgen vaccinees 2 and 3 years after vaccination. Three years post-vaccination PT-neutralising antibodies remained 4·6-fold (95% Confidence Interval (CI) 2·6-8·1) and 3·7-fold (95% CI 2·2-6·1) higher, PT-IgG antibodies 3·0-fold (95% CI 2·2-4·1) and 2·5-fold (95% CI 1·9-3·3) higher, and FHA-IgG antibodies 1·8-fold (95% CI 1·3-2·5) and 1·6-fold (95% CI 1·2-2·1) higher than baseline in aPgen and TdaPgen recipients, respectively. In the Tdapchem group, PT-neutralising and PT-IgG and FHA-IgG antibodies were back at baseline levels 2 years post-vaccination. Three years post-vaccination seroconversion rates for PT-neutralising antibodies were 65·0% (95% CI 44·1-85·9) and 55·0% (95% CI 33·2-76·8) in aPgen and TdaPgen recipients, respectively. INTERPRETATION: Considering the persistence of elevated antibody responses 3 years post-booster vaccination, genetically detoxified monovalent aPgen and TdaPgen vaccines can be expected to induce longer-lasting protection than chemically inactivated Tdap vaccines. FUNDING: BioNet-Asia.

Optimising a 6-plex tetanus-diphtheria-pertussis fluorescent bead-based immunoassay.

Small volume assays are required for large-scale research studies and in particular paediatric trials, where multiple measures are required from a single sample. Fluorescent bead-based technology (Bioplex/Luminex) allows high through-put and simultaneous quantification of multiple analytes in a single test. This technology uses sets of microspheres, each with a unique spectral address that can be coated with a different antigen of interest. Following the addition of a detector antibody, specific for the isotype of interest and labelled with R-Phycoerythrin, the bioplex reader determines the amounts of antigen-specific antibodies in each test sample relative to a reference standard. Here we outline the optimisations undertaken to establish a 6-plex fluorescent bead-based immunoassay that can accurately measure human IgG to individual tetanus-diphtheria-acellular pertussis (Tdap) antigens from 2 to 4 ul of human serum/ plasma. This protocol was adapted from previously published methods and aligns with current recommendations for developing pertussis-serological assays. To our knowledge, this is the first Tdap-specific multiplex immunoassay (MIA) established in Australia. All components were optimised and validated in-house including: microsphere preparation conditions, reference serum and QC development, and assay running.•Determining optimal antigen coating dose and conjugation method.•Optimising an in-house reference serum with clinically relevant titres.•Determining assay specificity and reproducibility.

PCV10 elicits Protein D IgG responses in Papua New Guinean children but has no impact on NTHi carriage in the first two years of life.

BACKGROUND: Nasopharyngeal colonisation with nontypeable Haemophilus influenzae (NTHi) is associated with development of infections including pneumonia and otitis media. The 10-valent pneumococcal conjugate vaccine (PCV10) uses NTHi Protein D (PD) as a carrier. Papua New Guinean children have exceptionally early and dense NTHi carriage, and high rates of NTHi-associated disease. Vaccination with PCV10 could potentially reduce NTHi carriage and disease in this population by inducing a NTHi PD immune response. METHODS: Serum and nasopharyngeal swabs were collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age. Children received PCV10 (n = 55) or PCV13 (not containing NTHi PD) (n = 46) at 1, 2 and 3 months of age. NTHi carriage density was measured in swabs by qPCR. Serum PD-IgG levels were measured by bead-based immunoassay. RESULTS: Papua New Guinean children did naturally develop PD-IgG antibodies whose levels were increased at 4 months of age with PCV10 vaccination at 1-2-3 months. Despite this, most children were colonised with NTHi by 4 months of age (~95%) regardless of being vaccinated with PCV10 or PCV13, and PCV10 had no impact on NTHi carriage density. CONCLUSION: Early vaccination of infants with PCV10 elicited a robust PD antibody response but this had no impact on NTHi carriage. TRIAL REGISTRATION: ClinicalTrials.gov CTN NCT01619462.

An observational study of antibody responses to a primary or subsequent pertussis booster vaccination in Australian healthcare workers.

Adult pertussis vaccination is increasingly recommended to control pertussis in the community. However, there is little data on the duration and kinetics of immunity to pertussis boosters in adults. We compared IgG responses to vaccination with a tetanus, low-dose diphtheria, low-dose acellular pertussis (Tdap) booster at 1 week, 1 month and 1 year post-vaccination in whole-cell (wP)-primed Australian paediatric healthcare workers who had received an adult Tdap booster 5-12 years previously, to those who received their first Tdap booster. Tdap vaccination was well tolerated in both groups. Previously boosted adults had significantly higher pre-vaccination IgG concentrations for all vaccine-antigens, and more were seropositive for pertussis toxin (PT)-specific IgG (≥ 5 IU/mL) (69.5%; 95% confidence interval (CI) 59.5-79.5) than adults in the naïve group (45.2%; 95% CI 32.8-57.5). Tdap vaccination significantly increased IgG responses 1 month post-vaccination in both groups. This increase was more rapid in previously boosted than in naïve adults, with geometric mean fold-increases in PT-IgG at 1 week post vaccination of 3.6 (95% CI 2.9-4.3) and 2.6 (95% CI 2.2-3.2), respectively. Antibody waning between 1 month and 1 year post-vaccination was similar between groups for IgG specific to PT and filamentous haemagglutinin (FHA), but was faster for IgG against pertactin (PRN) in the naïve group (GMC ratio 0.36; 95% CI 0.31-0.42) than the previously boosted group (GMC ratio 0.45; 95% CI 0.39-0.50). At baseline, all but one adult had protective IgG titres against tetanus toxin (TT) (≥ 0.1 IU/mL), and 75.6% in the previously boosted and 61.3% in the naïve group had protective IgG titres against diphtheria toxoid (DT) of ≥ 0.1 IU/mL. This study shows that pertussis immune memory is maintained up to 12 years after Tdap vaccination in wP-primed Australian adults. There was no evidence that pertussis immune responses waned faster after a booster dose. These findings support current recommendations of repeating Tdap booster vaccination in paediatric healthcare workers at least every 10 years. Clinical trials registry: ACTRN12615001262594.

Epidemiology of Escherichia coli Bacteremia: A Systematic Literature Review.

BACKGROUND: Escherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed. METHODS: A systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes. RESULTS: During the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100 000 person-years were >100 in 55-to-75-year-olds and >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes. CONCLUSIONS: This systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group.

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.

Corrigendum: Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea.

[This corrects the article DOI: 10.3389/fped.2020.00197.].

An observational study of the reactogenicity and immunogenicity of 13-valent pneumococcal conjugate vaccine in women of childbearing age in Papua New Guinea.

BACKGROUND: Maternal immunization with pneumococcal conjugate vaccine (PCV) may protect young infants in high-risk settings against the high risk of pneumococcal infections in early life. The aim of this study was to determine the safety and immunogenicity of 13-valent PCV (PCV13) in healthy women of childbearing age in PNG. METHODS: As part of this observational study, 50 non-pregnant women of childbearing age (18-45 yrs. old) living in the highlands of PNG were vaccinated with a single dose of PCV13. Local and systemic reactogenicity were assessed 24-48 h after vaccination. Venous blood samples were collected before and 1 month after vaccination to measure PCV13 serotype-specific IgG antibody concentrations. RESULTS: No severe adverse effects were reported during the 1-month follow-up period. IgG antibody concentrations significantly increased after vaccination for all PCV13 serotypes. One month after vaccination IgG antibody levels ≥2.5 µg/mL were reached in at least 75% of women for all PCV13 serotypes, except serotype 3, and ≥ 5 µg/mL in at least 75% of women for 7 serotypes (serotypes 6B, 9 V, 14, 18C, 19A, 19F and 23F). CONCLUSION: PCV13 is safe and immunogenic in women of childbearing age living in a high-risk setting in PNG. This supports the implementation of studies to investigate the safety and immunogenicity of maternal PCV vaccination in high-risk settings as a strategy to protect infants in these settings against the high risk of pneumococcal infections in early life. TRIAL REGISTRATION: NCT04183322 . Registered 3 December 2019 - Retrospectively registered.

Enhanced post-licensure safety surveillance of a new recombinant acellular pertussis vaccine licensed as a monovalent (aP, Pertagen®) and tetanus, reduced-dose diphtheria combination (TdaP, Boostagen®) vaccine for immunization of adolescents and adults in Thailand.

A new generation of recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin (PTgen) was licensed as a monovalent pertussis vaccine (aPgen; Pertagen®) and in combination with tetanus and reduced-dose diphtheria (TdaPgen; Boostagen®) for active immunization in individuals aged 11 years and older in Thailand in 2016. We here report post-marketing safety data on the use of the vaccines in individuals in the community obtained through active pharmacovigilance surveillance including pregnant women participating in a prospective observational study. Between May 2017 and February 2020 for TdaPgen and between June 2018 and February 2020 for aPgen, participating health care providers vaccinated and collected safety data for 11,429 exposed adolescents and adults. This included 1778 pregnant women. The incidence rate of adverse events following immunization (AEFIs) was 11.5 per 1000 of vaccinated individuals (95% confidence interval (95% CI) 9.7-13.6). AEFIs mostly concerned local pain at the injection site and muscle pain, and symptoms were mild and mostly resolved within a few days with no complications. The incidence rate of AEFIs in women vaccinated during pregnancy was 1.1 per 1000 (95% CI 0.3-4.1). Of 833 pregnant women vaccinated with recombinant aPgen or TdaPgen, 91.4% (95% CI 89.3-93.3) had uncomplicated pregnancies and 98.7% (95% CI 97.7-99.4) of the 855 babies delivered by these women were born healthy, which exceeds rates generally reported in Thailand. There were no vaccine-related serious adverse events reported during the surveillance period. In conclusion, active pharmacovigilance confirms that the recombinant pertussis vaccines aPgen (Pertagen) and TdaPgen (Boostagen) are safe in adolescents and adults, including pregnant women vaccinated in the second or third trimester of pregnancy.

Pneumococcal conjugate vaccine primes mucosal immune responses to pneumococcal polysaccharide vaccine booster in Papua New Guinean children.

INTRODUCTION: Invasive pneumococcal disease remains a major cause of hospitalization and death in Papua New Guinean (PNG) children. We assessed mucosal IgA and IgG responses in PNG infants vaccinated with pneumococcal conjugate vaccine (PCV) followed by a pneumococcal polysaccharide vaccine (PPV) booster. METHODS: Infants received 7-valent PCV (7vPCV) in a 0-1-2 (neonatal) or 1-2-3-month (infant) schedule, or no 7vPCV (control). At age 9 months all children received 23-valent PPV (23vPPV). IgA and IgG to 7vPCV and non-7vPCV (1, 5, 7F, 19A) serotypes were measured in saliva collected at ages 1, 2, 3, 4, 9, 10 and 18 months (131 children, 917 samples). Correlations were studied between salivary and serum IgG at 4, 10 and 18 months. RESULTS: Salivary IgA and IgG responses overall declined in the first 9 months. Compared to non-7vPCV recipients, salivary IgA remained higher in 7vPCV recipients for serotypes 4 at 3 months, 6B at 3 months (neonatal), and 14 at 3 (neonatal), 4 and 9 months (infant); and for salivary IgG for serotypes 4 at 3, 4 and 9 months, 6B at 9 months, 14 at 4 (neonatal) and 9 months, 18C at 3, 4, and 9 (infant) months, and 23F at 4 months. Following 23vPPV, salivary 7vPCV-specific IgA and IgG increased in 7vPCV-vaccinated children but not in controls; and salivary IgA against non-PCV serotypes 5 and 7F increased in 7vPCV recipients and non-recipients. Salivary and serum IgG against 7vPCV-serotypes correlated in 7vPCV-vaccinated children at 4 and 10 months of age. CONCLUSIONS: PCV may protect high-risk children against pneumococcal colonization and mucosal disease by inducing mucosal antibody responses and priming for mucosal immune memory that results in mucosal immune responses after booster PPV. Saliva can be a convenient alternative sample to serum to study PCV-induced systemic IgG responses.

Clinical Protocol for a Longitudinal Cohort Study Employing Systems Biology to Identify Markers of Vaccine Immunogenicity in Newborn Infants in The Gambia and Papua New Guinea.

Background: Infection contributes to significant morbidity and mortality particularly in the very young and in low- and middle-income countries. While vaccines are a highly cost-effective tool against infectious disease little is known regarding the cellular and molecular pathways by which vaccines induce protection at an early age. Immunity is distinct in early life and greater precision is required in our understanding of mechanisms of early life protection to inform development of new pediatric vaccines. Methods and Analysis: We will apply transcriptomic, proteomic, metabolomic, multiplex cytokine/chemokine, adenosine deaminase, and flow cytometry immune cell phenotyping to delineate early cellular and molecular signatures that correspond to vaccine immunogenicity. This approach will be applied to a neonatal cohort in The Gambia (N ~ 720) receiving at birth: (1) Hepatitis B (HepB) vaccine alone, (2) Bacille Calmette Guerin (BCG) vaccine alone, or (3) HepB and BCG vaccines, (4) HepB and BCG vaccines delayed till day 10 at the latest. Each study participant will have a baseline peripheral blood sample drawn at DOL0 and a second blood sample at DOL1,-3, or-7 as well as late timepoints to assess HepB vaccine immunogenicity. Blood will be fractionated via a "small sample big data" standard operating procedure that enables multiple downstream systems biology assays. We will apply both univariate and multivariate frameworks and multi-OMIC data integration to identify features associated with anti-Hepatitis B (anti-HB) titer, an established correlate of protection. Cord blood sample collection from a subset of participants will enable human in vitro modeling to test mechanistic hypotheses identified in silico regarding vaccine action. Maternal anti-HB titer and the infant microbiome will also be correlated with our findings which will be validated in a smaller cohort in Papua New Guinea (N ~ 80). Ethics and Dissemination: The study has been approved by The Gambia Government/MRCG Joint Ethics Committee and The Boston Children's Hospital Institutional Review Board. Ethics review is ongoing with the Papua New Guinea Medical Research Advisory Committee. All de-identified data will be uploaded to public repositories following submission of study output for publication. Feedback meetings will be organized to disseminate output to the study communities. Clinical Trial Registration: Clinicaltrials.gov Registration Number: NCT03246230.

The impact of routine childhood immunization with higher-valent pneumococcal conjugate vaccines on antimicrobial-resistant pneumococcal diseases and carriage: a systematic literature review.

Introduction: The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in childhood immunization programs reduced antimicrobial-resistant pneumococcal infections by vaccine serotypes. However, emerging antimicrobial-resistant non-vaccine serotypes, particularly serotype 19A, attenuated the overall effect. In 2010, higher-valent PCVs became available containing serotypes that are prone to become antimicrobial-resistant, like serotype 7F in PCV10 and PCV13, and serotype 19A in PCV13.Areas covered: This review evaluated literature published between June 1, 2008 and June 1, 2017 reporting on the effect of PCV10 or PCV13 implementation in routine infant immunization schedules on antimicrobial-resistant invasive pneumococcal disease (IPD), otitis media (OM), and nasopharyngeal carriage (NPC) in children and adults.Expert opinion: In countries with relatively high prior pneumococcal antimicrobial resistance (AMR), PCV13 childhood vaccination programs have reduced antimicrobial-resistant IPD, OM, and NPC in children and IPD in adults. The effectiveness of PCV13 against serotype 19A is likely an important contributing factor. Only few studies have documented the impact of PCV10 on AMR. Multiple factors may influence observed decreases in pneumococcal AMR including antimicrobial stewardship, case definition, time since PCV10/13 introduction, and pre-PCV10/13 AMR levels. This review emphasizes the importance of including impact on AMR when evaluating the full public health of pneumococcal vaccination programs.

Dynamic molecular changes during the first week of human life follow a robust developmental trajectory.

Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from <1 ml of blood, a volume readily obtained from newborns. Indexing to baseline and applying innovative integrative computational methods reveals dramatic changes along a remarkably stable developmental trajectory over the first week of life. This is most evident in changes of interferon and complement pathways, as well as neutrophil-associated signaling. Validated across two independent cohorts of newborns from West Africa and Australasia, a robust and common trajectory emerges, suggesting a purposeful rather than random developmental path. Systems biology and innovative data integration can provide fresh insights into the molecular ontogeny of the first week of life, a dynamic developmental phase that is key for health and disease.

Immunogenicity and Immune Memory after a Pneumococcal Polysaccharide Vaccine Booster in a High-Risk Population Primed with 10-Valent or 13-Valent Pneumococcal Conjugate Vaccine: A Randomized Controlled Trial in Papua New Guinean Children.

We investigated the immunogenicity, seroprotection rates and persistence of immune memory in young children at high risk of pneumococcal disease in Papua New Guinea (PNG). Children were primed with 10-valent (PCV10) or 13-valent pneumococcal conjugate vaccines (PCV13) at 1, 2 and 3 months of age and randomized at 9 months to receive PPV (PCV10/PPV-vaccinated, n = 51; PCV13/PPV-vaccinated, n = 52) or no PPV (PCV10/PPV-naive, n = 57; PCV13/PPV-naive, n = 48). All children received a micro-dose of PPV at 23 months of age to study the capacity to respond to a pneumococcal challenge. PPV vaccination resulted in significantly increased IgG responses (1.4 to 10.5-fold change) at 10 months of age for all PPV-serotypes tested. Both PPV-vaccinated and PPV-naive children responded to the 23-month challenge and post-challenge seroprotection rates (IgG ≥ 0.35 µg/mL) were similar in the two groups (80⁻100% for 12 of 14 tested vaccine serotypes). These findings show that PPV is immunogenic in 9-month-old children at high risk of pneumococcal infections and does not affect the capacity to produce protective immune responses. Priming with currently available PCVs followed by a PPV booster in later infancy could offer improved protection to young children at high risk of severe pneumococcal infections caused by a broad range of serotypes.

Safety and Immunogenicity of Pneumococcal Conjugate Vaccines in a High-risk Population: A Randomized Controlled Trial of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccine in Papua New Guinean Infants.

BACKGROUND: There are little data on the immunogenicity of PCV10 and PCV13 in the same high-risk population. METHODS: PCV10 and PCV13 were studied head-to-head in a randomized controlled trial in Papua New Guinea in which 262 infants received 3 doses of PCV10 or PCV13 at 1, 2, and 3 months of age. Serotype-specific immunoglobulin G (IgG) concentrations, and pneumococcal and nontypeable Haemophilus influenzae (NTHi) carriage were assessed prevaccination and at 4 and 9 months of age. Infants were followed up for safety until 9 months of age. RESULTS: One month after the third dose of PCV10 or PCV13, ˃80% of infants had IgG concentrations ≥0.35µg/mL for vaccine serotypes, and 6 months postvaccination IgG concentrations ≥0.35 µg/mL were maintained for 8/10 shared PCV serotypes in > 75% of children vaccinated with either PCV10 or PCV13. Children carried a total of 65 different pneumococcal serotypes (plus nonserotypeable). At 4 months of age, 92% (95% confidence interval [CI] 85-96) of children vaccinated with PCV10 and 81% (95% CI 72-88) vaccinated with PCV13 were pneumococcal carriers (P = .023), whereas no differences were seen at 9 months of age, or for NTHi carriage. Both vaccines were well tolerated and not associated with serious adverse events. CONCLUSIONS: Infant vaccination with 3 doses of PCV10 or PCV13 is safe and immunogenic in a highly endemic setting; however, to significantly reduce pneumococcal disease in these settings, PCVs with broader serotype coverage and potency to reduce pneumococcal carriage are needed. CLINICAL TRIALS REGISTRATION: NCT01619462.

Antibody persistence after vaccination of adolescents with monovalent and combined acellular pertussis vaccines containing genetically inactivated pertussis toxin: a phase 2/3 randomised, controlled, non-inferiority trial.

BACKGROUND: The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. METHODS: We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12-17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64-88) participants in the aP(PTgen/FHA) group and 41 (81%, 70-92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1-16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71-93 and 64%, 51-77, respectively) and TdaP(PTgen/FHA) group (75%, 63-87 and 56%, 42-70, respectively) than in the Tdap group (4%, 0-9, p<0·0001, and 28%, 16-41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. INTERPRETATION: A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. FUNDING: BioNet-Asia.