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

Idoko, Olubukola T.; Smolen, Kinga K.; Wariri, Oghenebrume; Imam, Abdulazeez; Shannon, Casey P.; Dibassey, Tida; Diray‐Arce, Joann; Darboe, Alansana; Strandmark, Julia; Ben‐Othman, Rym; Odumade, Oludare A.; McEnaney, Kerry; Amenyogbe, Nelly; Pomat, William; Haren, Simon van; Sánchez-Schmitz, Guzman; Brinkman, Ryan R.; Steen, Hanno; Hancock, Robert E. W.; Tebbutt, Scott J.; Richmond, Peter; Biggelaar, Anita H. J. van den; Kollmann, Tobias R.; Levy, Ofer; Ozonoff, Al; Kampmann, Beate

doi:10.3389/fped.2020.00197

Cited by 15 publications

(16 citation statements)

References 28 publications

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“…Thirty and nineteen healthy, term newborns were enrolled at the Medical Research Council (MRC) Unit The Gambia at London School of Hygiene and Tropical Medicine and at the Institute for Medical Research (IMR) in Goroka, Papua New Guinea in accordance, with a local Ethics Committee-approved protocol (MRC SCC 1436 and IMR IRB#1515 and MRAC #16.14). A detailed description of the protocol has been published ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…Finally, metabolomics can complement the characterization of complex systems measurements of the effect of a defined immune perturbation such as vaccination ( Figure 1). Such an approach is particularly promising in the newborn, given our recent demonstration of marked changes in numerous metabolic pathways across the first week of human life [47], a time of marked susceptibility to infection and of receipt of multiple vaccines, such as via the Expanded Program on Immunization-which includes Bacille Calmette-Guérin vaccine, hepatitis B vaccine, and polio vaccine) [48,49]. In light of these proof-of-concept examples, further metabolomic discovery and targeted metabolite validation may provide novel biomarkers of infectious diseases and successful immunization.…”

Section: Metabolomics-an Emerging Tool To Complement Other Systems Immentioning

confidence: 99%

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

et al. 2020

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Approaches to the identification of metabolites have progressed from early biochemical pathway evaluation to modern high-dimensional metabolomics, a powerful tool to identify and characterize biomarkers of health and disease. In addition to its relevance to classic metabolic diseases, metabolomics has been key to the emergence of immunometabolism, an important area of study, as leukocytes generate and are impacted by key metabolites important to innate and adaptive immunity. Herein, we discuss the metabolomic signatures and pathways perturbed by the activation of the human immune system during infection and vaccination. For example, infection induces changes in lipid (e.g., free fatty acids, sphingolipids, and lysophosphatidylcholines) and amino acid pathways (e.g., tryptophan, serine, and threonine), while vaccination can trigger changes in carbohydrate and bile acid pathways. Amino acid, carbohydrate, lipid, and nucleotide metabolism is relevant to immunity and is perturbed by both infections and vaccinations. Metabolomics holds substantial promise to provide fresh insight into the molecular mechanisms underlying the host immune response. Its integration with other systems biology platforms will enhance studies of human health and disease.

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“…The Expanded Program on Immunization Consortium (EPIC) study 002 (EPIC002) clinical protocol has been previously described (53), and the study is registered on clinicaltrials.gov as NCT03246230. The study's primary goal was to assess vaccine immunogenicity in newborns in 4 different vaccine groups (no vaccines at birth (i.e., delayed immunization), Hepatitis B vaccine (HBV) alone at birth, BCG alone at birth, and both (HBV and BCG) at birth; with n = 180 per group).…”

Section: Study Design and Sample Collectionmentioning

confidence: 99%

“…Partnering as international collaborators via the Expanded Program on Immunization Consortium (EPIC), we conducted the EPIC002 study, a prospective study to characterize immunologic biomarkers in newborn infants followed across a four-month period (53). We measured ADA1 and ADA2 in infant plasma to determine age-dependent changes in early life.…”

Section: Introductionmentioning

confidence: 99%

Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life

et al. 2021

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BackgroundHuman adenosine deaminases (ADAs) modulate the immune response: ADA1 via metabolizing adenosine, a purine metabolite that inhibits pro-inflammatory and Th1 cytokine production, and the multi-functional ADA2, by enhancing T-cell proliferation and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is known about the ontogeny of ADA concentrations.MethodsIn a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated to ADA concentrations.ResultsADA2 demonstrated a steady rise across the first months of life, while ADA1 concentration significantly decreased 0.79-fold across the first week then increased 1.4-fold by four months of life. Males demonstrated significantly higher concentrations of ADA2 (1.1-fold) than females at four months; newborns with early-term (37 to <39 weeks) and late-term (≥41 weeks) gestational age demonstrated significantly higher ADA1 at birth (1.1-fold), and those born to mothers with advanced maternal age (≥35 years) had lower plasma concentrations of ADA2 at one month (0.93-fold). Plasma ADA1 concentrations were positively correlated with plasma CXCL8 during the first week of life, while ADA2 concentrations correlated positively with TNFα, IFNγ and CXCL10, and negatively with IL-6 and CXCL8.ConclusionsThe ratio of plasma ADA2/ADA1 concentration increased during the first week of life, after which both ADA1 and ADA2 increased across the first four months of life suggesting a gradual development of Th1/Th2 balanced immunity. Furthermore, ADA1 and ADA2 were positively correlated with cytokines/chemokines during the first week of life. Overall, ADA isoforms demonstrate robust ontogeny in newborns and infants but further mechanistic studies are needed to clarify their roles in early life immune development and the correlations with sex, gestational age, and maternal age that were observed.

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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

Cited by 15 publications

References 28 publications

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

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

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life

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