Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity (EPIC-HIPC)

• ClinicalTrials.gov Identifier: NCT03246230
• Recruitment Status: Active, not recruiting
• First Posted: August 11, 2017
• Last Update Posted: March 21, 2022
• Sponsor: Boston Children's Hospital
• Collaborators: Medical Research Council Unit, The Gambia; University of British Columbia; Institute for Medical Research, Papua New Guinea; The University of Western Australia
• Information provided by (Responsible Party): Ofer Levy, Boston Children's Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Newborn Vaccine Immunogenicity	Biological: Hepatitis B vaccine (HBV); Biological: Bacillus Calmette-Guérin (BCG)	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 890 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Newborn infants will have delayed immunization, with catch-up immunization at day of life 7 (DOL7), or immunization at birth with hepatitis B vaccine (HBV), Bacille Calmette-Guérin (BCG) or (HBV +BCG). All participants will have peripheral blood collected at birth (DOL0) and each group will be divided into sub-groups with follow-up peripheral blood collection at DOL1, DOL3, or DOL7.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity
• Actual Study Start Date: September 6, 2017
• Estimated Primary Completion Date: June 30, 2022
• Estimated Study Completion Date: September 30, 2022

Arms and Interventions

Arm	Intervention/treatment
No Intervention: 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.
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.	Biological: Hepatitis B vaccine (HBV); 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.	Biological: Bacillus Calmette-Guérin (BCG); 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.	Biological: Hepatitis B vaccine (HBV); Licensed pediatric HBV vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.; Biological: Bacillus Calmette-Guérin (BCG); Licensed BCG vaccine will be administered at birth (Day of Life 0) or delayed to Day of Life 7.

Outcome Measures

Primary Outcome Measures :

1. Molecular signature correlating with anti-hepatitis B vaccine antibody response [ Time Frame: 1 month of age ]
   We will employ bioinformatics to define molecular signatures correlating with anti-HBV responses

Eligibility Criteria

• Ages Eligible for Study: up to 1 Day (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

Gambia

Medical Research Council Unit, The Gambia

Fajara, Gambia, 000273

Papua New Guinea

Institute for Medical Research

Goroka, Eastern Highlands, Papua New Guinea

Sponsors and Collaborators

Boston Children's Hospital

Medical Research Council Unit, The Gambia

University of British Columbia

Institute for Medical Research, Papua New Guinea

The University of Western Australia

Investigators

• Principal Investigator: Ofer Levy, MD, PhD; Boston Children's Hospital
• Study Director: Tobias R Kollmann, MD, PhD; The University of Western Australia
• Study Chair: Beate Kampmann, MD, PhD; Medical Research Council (MRC) Gambia

More Information

Additional Information:

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

Publications:

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). pii: 20140340. doi: 10.1098/rstb.2014.0340. Review.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Erratum in: Front Pediatr. 2020 Nov 17;8:610461.

• Responsible Party: Ofer Levy, Staff Physician, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT03246230
• Other Study ID Numbers: IRB-P00024239
• First Posted: August 11, 2017
• Last Update Posted: March 21, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ofer Levy, Boston Children's Hospital:

newborn vaccine responses

Additional relevant MeSH terms:

BCG Vaccine; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs