Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity

NCT ID: NCT03246230

Last Updated: 2023-12-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 911 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-06
• Study Completion Date: 2022-08-29

Brief Summary

Infection is the most common cause of death in early life, especially for newborns and can be reduced by immunization but insufficient knowledge of how vaccines protect the very young limits their optimal use. To gain insight into how vaccines induce protection of the most vulnerable, this National Institutes of Health (NIH)/National Institute of Allergy & Infectious Diseases (NIAID)-funded Human Immunology Project Consortium (HIPC) study, based at Boston Children's Hospital and conducted by the Expanded Program on Immunization Consortium (EPIC), employs two novel approaches studying newborn responses to hepatitis B vaccine (HBV): (a) systems biology that uses technologies which comprehensively measure global changes in molecules such as transcriptomics (RNA) and proteomics (proteins), as well as cell composition of the blood and (b) use of human newborn blood components, collected prior to immunization, to model vaccine responses in vitro (outside the body). Characterizing vaccine-induced molecular patterns ("signatures") that correspond to vaccine-mediated protection will accelerate development and optimization of vaccines against early life infections of major global health importance.

Detailed Description

While the greatest number of vaccines is administered to the very young, vaccine preventable infections remain a major cause of morbidity and mortality, especially for the newborn. To improve vaccine-mediated protection early in life, the investigators will identify biomarkers that predict protective efficacy and garner insight into the underlying mechanisms of vaccine-mediated protection. Systems biology approaches ("OMICs") applied to vaccinology, i.e., systems vaccinology, has revolutionized the field with an unbiased identification of pathways relevant to vaccine-induced immune responses. However, thus far systems vaccinology has focused primarily on adults, with few studies conducted in children and infants, and none in newborns. This study will bridge this gap by conducting a comprehensive systems vaccinology study in newborns. Specifically, the investigators will determine the molecular pathways that are associated with successful neonatal immunization with hepatitis B virus vaccine (HBV). HBV is the ideal model because i) it is highly (>90%) effective; ii) it has a well-established correlate of protection (CoP; anti-hepatitis surface antigen antibody (anti-HBs)); iii) there is substantial variation in anti-HBs titers and quantifiable inter-subject variability is essential for systems biological approaches; iv) it is highly relevant as HBV is given at birth in the U.S. and most developing countries; v) it is amenable to in vivo manipulation with another regularly administered neonatal vaccine, Bacille Calmette-Guérin (BCG), which will greatly enhance detection of relevant signatures. As complex networks of functional interactions among genes and proteins drive the response to immunization, the investigators will integrate transcriptomic, proteomic and immune phenotyping approaches. Importantly, the investigators have successfully adapted these experimental platforms to be fully operational within the small blood volumes obtainable in newborns. The investigators have also developed in vitro systems amenable to experimental manipulation on the cellular and molecular level to identify cause-effect relationships. Pilot data prove feasibility of collecting the relevant high-quality samples according to stringent standard operating procedures, processing them and delivering cogent OMIC data suggesting vaccine-specific 'signatures' in the human newborn. This HIPC will identify biomarkers of neonatal HBV immunogenicity by pursuing the following Overall Specific Aims:

• Aim 1. Characterize pre-vaccine OMIC and immune signatures in vivo that predict immunogenicity of HBV in human newborns. In adult systems vaccinology studies, baseline immune status of vaccine recipients predicted vaccine immunogenicity at least as well or even better than changes induced by the vaccine. For Aim 1 the investigators will determine the pre-vaccine (Day 0) characteristics of whole blood gene expression, plasma proteome as well as the composition of the white blood cell compartment and their functional status in correlation with the HBV-induced neonatal antibody response.
• Aim 2. Characterize the post-vaccine impact of HBV on OMIC and immune signatures in vivo that predict immunogenicity of HBV in human newborns. In adults, analysis of vaccine-induced signatures (i.e. post-vaccine) has provided new insights for several vaccines, including HBV. The investigators will for the first time apply this approach to newborns and expand it by manipulating the neonatal response to HBV in vivo by co-administering BCG, as it substantially changes immunogenicity of HBV thereby testing cause-effect relationships in vivo. For Aim 2 the investigators will characterize whole blood gene expression and the plasma and leukocyte proteome as well as white blood cell composition and functional status at Days 1, -3 and -7 postvaccine contrasting infants that received nothing (delayed vaccines to 7 days of age), HBV, BCG or (HBV + BCG) at birth and correlate this with anti-HBs titers.
• Aim 3. Interrogate functional correlations identified in silico via novel human in vitro platforms that accurately model age-specific vaccine responses and are amenable to a wide range of experimental manipulation allowing mechanistic cause-effect relationships to be probed on the molecular level.

Overall, these integrated studies will identify vaccine-induced molecular pathways correlating with protective immune responses in newborns and will generate and test new mechanistic hypotheses regarding vaccine action in vivo and in vitro. This study will ultimately inform, accelerate and optimize early life immunization resulting in major public health benefit.

Conditions

Newborn Vaccine Immunogenicity

Keywords

newborn vaccine responses

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

NO VACCINES AT BIRTH

These will be newborns who will not receive any vaccines at birth and will have delayed immunization with catch-up (i.e., HBV, BCG and polio vaccine) by Day of Life 7.

Group Type: NO_INTERVENTION

No interventions assigned to this group

HBV VACCINE AT BIRTH

Participants in this arm will receive licensed hepatitis B vaccine (HBV) at birth (Day of Life (DOL)-0) with catch up immunization (i.e., BCG and polio vaccine) at DOL-1, -3, or -7.

Group Type: OTHER

Hepatitis B vaccine (HBV)

Intervention Type: BIOLOGICAL

Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

BCG VACCINE AT BIRTH

Participants in this arm will receive licensed Bacillus Calmette-Guérin (BCG) vaccine at birth (Day of Life(DOL)-0) with catch up immunization (i.e., HBV and polio vaccine) at DOL-1, -3 or- 7.

Group Type: OTHER

Bacillus Calmette-Guérin (BCG)

Intervention Type: BIOLOGICAL

Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

(HBV + BCG) VACCINES AT BIRTH

Participants in this arm will receive licensed hepatitis B vaccine (HBV) and licensed Bacillus Calmette-Guérin (BCG) vaccine at birth (Day of Life (DOL- 0) with catch up immunization (i.e., polio vaccine) at DOL-1, -3, or -7.

Group Type: OTHER

Hepatitis B vaccine (HBV)

Intervention Type: BIOLOGICAL

Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

Bacillus Calmette-Guérin (BCG)

Intervention Type: BIOLOGICAL

Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

Interventions

Hepatitis B vaccine (HBV)

Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

Intervention Type: BIOLOGICAL

Bacillus Calmette-Guérin (BCG)

Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• <24 hours of age
• >37 weeks gestational age
• HIV unexposed
• Healthy (no malformations, normal temperature range and vital signs for age)

Exclusion Criteria

• Premature (<37 weeks gestational age)
• Hepatitis B antigen-positive mother
• HIV-positive or HIV-exposed
• Febrile, unstable vital signs

• Minimum Eligible Age: 0 Days
• Maximum Eligible Age: 1 Day
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Medical Research Council Unit, The Gambia

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: collaborator

Institute for Medical Research, Papua New Guinea

UNKNOWN

Sponsor Role: collaborator

The University of Western Australia

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Ofer Levy

Staff Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ofer Levy, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Tobias R Kollmann, MD, PhD

Role: STUDY_DIRECTOR

The University of Western Australia

Beate Kampmann, MD, PhD

Role: STUDY_CHAIR

Medical Research Council (MRC) Gambia

Locations

Institute for Medical Research

Goroka, Eastern Highlands Province, Papua New Guinea

Medical Research Council Unit, The Gambia

Fajara, , The Gambia

Countries

Papua New Guinea; The Gambia

References

Amenyogbe N, Levy O, Kollmann TR. Systems vaccinology: a promise for the young and the poor. Philos Trans R Soc Lond B Biol Sci. 2015 Jun 19;370(1671):20140340. doi: 10.1098/rstb.2014.0340.

Reference Type: BACKGROUND

PMID: 25964462 (View on PubMed)

Lee AH, Shannon CP, Amenyogbe N, Bennike TB, Diray-Arce J, Idoko OT, Gill EE, Ben-Othman R, Pomat WS, van Haren SD, Cao KL, Cox M, Darboe A, Falsafi R, Ferrari D, Harbeson DJ, He D, Bing C, Hinshaw SJ, Ndure J, Njie-Jobe J, Pettengill MA, Richmond PC, Ford R, Saleu G, Masiria G, Matlam JP, Kirarock W, Roberts E, Malek M, Sanchez-Schmitz G, Singh A, Angelidou A, Smolen KK; EPIC Consortium; Brinkman RR, Ozonoff A, Hancock REW, van den Biggelaar AHJ, Steen H, Tebbutt SJ, Kampmann B, Levy O, Kollmann TR. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory. Nat Commun. 2019 Mar 12;10(1):1092. doi: 10.1038/s41467-019-08794-x.

Reference Type: BACKGROUND

PMID: 30862783 (View on PubMed)

Montante S, Ben-Othman R, Amenyogbe N, Angelidou A, van den Biggelaar A, Cai B, Chen Y, Darboe A, Diray-Arce J, Ford R, Idoko O, Lee A, Lo M, McEnaney K, Malek M, Martino D, Masiria G, Odumade OA, Pomat W, Shannon C, Smolen K, Consortium TE, Ozonoff A, Richmond P, Tebbutt S, Levy O, Kampmann B, Brinkman R, Kollmann T. Breastfeeding and Neonatal Age Influence Neutrophil-Driven Ontogeny of Blood Cell Populations in the First Week of Human Life. J Immunol Res. 2024 Jul 23;2024:1117796. doi: 10.1155/2024/1117796. eCollection 2024.

Reference Type: DERIVED

PMID: 39081632 (View on PubMed)

Idoko OT, Smolen KK, Wariri O, Imam A, Shannon CP, Dibassey T, Diray-Arce J, Darboe A, Strandmark J, Ben-Othman R, Odumade OA, McEnaney K, Amenyogbe N, Pomat WS, van Haren S, Sanchez-Schmitz G, Brinkman RR, Steen H, Hancock REW, Tebbutt SJ, Richmond PC, van den Biggelaar AHJ, Kollmann TR, Levy O, Ozonoff A, Kampmann B. 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. Front Pediatr. 2020 Apr 30;8:197. doi: 10.3389/fped.2020.00197. eCollection 2020.

Reference Type: DERIVED

PMID: 32426309 (View on PubMed)

Related Links

https://www.niaid.nih.gov/research/human-immunology-project-consortium

Human Immunology Project Consortium/National Institute of Allergy \& Infectious Diseases

https://www.childrenshospital.org/research/departments/pediatrics-research/precision-vaccines-program

Precision Vaccines Program, Boston Children's Hospital

https://immunespace.org

Data, Tools \& Resources related to NIH/NIAID Human Immunology Project Consortium

Other Identifiers

IRB-P00024239

Identifier Type: -

Identifier Source: org_study_id