A Trial Investigating the Influence of BCG and Hepatitis B Immunisation at Birth on Neonatal Immune Responses: The Early Life Vaccines and Immunity Study

Study Overview
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Brief Summary
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Neonatal morbidity and mortality from infectious diseases is of global concern. Childhood disease-specific immunisation is irrefutably linked to the decline in deaths from these targeted infections over the last century. However, neonatal immunisation is limited, in part, by the impaired adaptive immune function in this age group. There is now an expanding body of evidence for heterologous ('non-specific') effects of various vaccines used in childhood. This refers to the immunomodulatory capabilities of vaccines to influence immune outcomes beyond the vaccine's specific targeted disease. The underlying immunological mechanisms responsible for these effects are incompletely understood, but evidence is mounting that the innate immune system is central to these observed effects. This study is a randomised controlled trial designed to determine the influence of two commonly administered neonatal immunisations, BCG and Hepatitis B vaccine, given at birth, on the neonatal immune responses to non-specific antigens. The investigators will recruit 200 newborns at the Mercy Hospital for Women in Melbourne, Australia over a 1-year period. These babies will be allocated randomly to one of 4 groups, receiving these 2 vaccines in different combinations, at 2 set time points. (at birth and 1 week post randomisation) A blood sample will be taken at 1-week post randomisation for in vitro immunological analyses. This study will improve current understanding of the influence of vaccines on neonatal immunity and will help develop strategies exploiting beneficial heterologous ('non-specific') effects to improve protection against infection in the very young.

Official Title
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A Randomised, Controlled Trial Investigating the Influence of BCG (Bacillus Calmette-Guérin) and Hepatitis B Immunisation at Birth on Neonatal Immune Responses

Conditions
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Innate Immune Response

Intervention / Treatment
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* Drug: BCG Vaccine
* Drug: Hepatitis B Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: English speaking parent Planned travel to a TB (Tuberculosis) endemic country within the infant's first 5 years of life An informed consent form must be signed and dated by the infant's mother after the nature of the study has been explained and prior to any study assessments/procedures The infant's mother has screened negative for HIV during this pregnancy The infant's mother has screened negative for Hepatitis B during this pregnancy There is no known household contact infected with Hepatitis B Born no earlier than eight weeks before estimated date of delivery Birth weight >1500g Delivered vaginally Singleton pregnancy Exclusion Criteria: Known or suspected HIV infection Treatment with corticosteroids or other immunosuppressive therapy, including monoclonal antibodies against tumour necrosis factor---alpha (TNF---alpha) (e.g. infliximab, etanercept, adalimumab). Born to a mother treated with bDMARDs (biological Disease- Modifying Anti-Rheumatic drugs) (e.g. TNF---alpha blocking monoclonal antibodies) in the 3rd trimester Congenital cellular immunodeficiencies including specific deficiencies of the interferon gamma pathway Malignancies involving bone marrow or lymphoid systems Serious underlying illness including severe malnutrition Medically unstable Generalised septic skin disease and skin conditions such as eczema, dermatitis and psoriasis Significant febrile illness Also excluded are infants with: A mother who is immunosuppressed; A mother who has received Intravenous immunoglobulins during her pregnancy A family history of immunodeficiency; Consanguineous parents. Mother who is having a planned Caesarean Section A home address more than 40 minutes drive from the Mercy hospital for Women and are unwilling to return to hospital for infant blood sampling

Ages Eligible for Study
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Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>BCG vaccine, 0,05ml intradermally at birth | Drug: BCG Vaccine<br>* intradermal vaccination<br>* Other names: Bacillus-Calmette-Guerin;|
| Active Comparator: Group 2<br>BCG vaccine, 0,05ml intradermally at birth Hepatitis B vaccine, 5 micrograms, intramuscularly at birth | Drug: BCG Vaccine<br>* intradermal vaccination<br>* Other names: Bacillus-Calmette-Guerin;Drug: Hepatitis B Vaccine<br>* intramuscular vaccination<br>* Other names: HB-Vax-II;|
| Active Comparator: Group 3<br>Hepatitis B vaccine, 5 micrograms, intramuscularly at birth | Drug: Hepatitis B Vaccine<br>* intramuscular vaccination<br>* Other names: HB-Vax-II;|
| No Intervention: Group 4<br>No birth vaccines | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cytokine concentrations (pg/ml) in response to in-vitro stimulation with a range of antigens | Four hours after blood samples are collected, they will be stimulated with different concentrations of infective antigens for 20hrs. (eg killed S.aureus, S. pneumoniae, E. Coli, Haemophilus Influenza B, Group B streptococcus, C. albicans), BCG, Hepatitis B sAg). Cytokine expression will be analysed in supernatants by Luminex -based multiplex assays. The cytokines that will be measured: Interleukin-1 beta, Interleukin-1ra, Interleukin-6, Interleukin-8, Macrophage/Monocyte Chemoattractant Protein-1(MCP-1), Macrophage Inflammatory Protein (MIP) -1 alpha, MIP-1 beta, Interferon(IFN) gamma, Interleukin-10, Macrophage migration inhibitory factor (MIF), Monokine induced by interferon (MIG), Tumour necrosis factor (TNF) alpha | 7 (+-4) days post randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG, neonates, Hepatitis B vaccine, vaccines, immunity, immune response, Bacille- Calmette-Guerin