Regulation of Immunity Induced by BCG Vaccination of Newborns

Willem Hanekom, M.B.Ch.B.

University of Cape Town

Funded in March, 2004: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

ABSTRACT

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Regulation of Immunity Induced by BCG Vaccination of Newborns

Tuberculosis (TB) kills 1.5 million people worldwide each year. Incomplete understanding of protective host immunity against TB is hampering development of novel, effective vaccines to control this epidemic.

As a first step in vaccine development, Dr. Hanekom’s group aims to describe immune correlates of protection induced by the only current vaccine, Mycobacterium bovis BCG. The researchers have already collected, processed and stored blood from 5,675 10-week old South African infants, routinely vaccinated with BCG at birth. Infants who  subsequently develop TB, following exposure to adults with the disease, will be identified—these infants will not have been protected by the vaccine. A control group of infants protected by the vaccine will also be identified, infants who have remained healthy despite exposure. The investigators will retrieve blood, stored from 10 weeks of age, of protected and unprotected infants and compare immunity in the 2 groups.

Dr. Hanekom’s group will examine immune responses conventionally associated with protection against mycobacteria, and look for novel immune correlates of protection with DNA micro-array technology. However, based on their preliminary data and on recent evidence that regulatory CD4+CD25+ T cells (TRegs) critically determine the outcome of intracellular infections, they will also investigate regulation of this immunity. Their hypothesis is that BCG vaccination of newborns results in a spectrum of functional TReg induction. It is proposed that the magnitude of this response correlates inversely with conventional BCG-specific immunity, and may ultimately be a “negative” correlate of vaccine efficacy.

INVESTIGATOR BIOGRAPHIES

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Willem Hanekom, M.B.Ch.B.

Dr. Willem Hanekom qualified as a pediatrician at the University of Cape Town in South Africa. He then completed a clinical pediatric infectious diseases fellowship at Northwestern University in Chicago. While a research associate at Rockefeller University in New York, he completed studies of dendritic cell interactions with Mycobacterium tuberculosis. During this time he also developed international projects aimed at characterizing host immune responses induced by BCG.

Dr. Hanekom has continued to work on these projects while an Assistant Professor in Clinical Pediatrics, Microbiology and Immunology at the University of Miami. He also holds an appointment at the University of Cape Town, South Africa, where he will take part in novel TB vaccine trials.

FINDINGS

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Lay Results:
Our aim was to look at whether the only available vaccine against tuberculosis (TB), BCG, stimulates the immune system to make as so-called “regulatory CD4+ T cells”, or “Tregs.” These white blood cells are very important for controlling the immune system after a vaccination. This means the cells make sure that the vaccine does not cause too much, or too little, immunity. The latter immunity, in turn, has to protect the vaccinated person against the disease for which he/she is vaccinated.

We tested blood from 10 week-old infants, routinely vaccinated with BCG at birth, and showed that 3 distinct types of Tregs form after vaccination. These 3 types of Tregs differ in how they control immunity. We believe that protection against childhood tuberculosis, afforded by newborn vaccination with BCG, involves a dynamic balance between immunity that protects against TB, and Tregs. We further propose that all 3 Treg populations should be measured when testing in the lab whether a TB vaccine will work or not.

Scientific Results:
To assess whether vaccination of human newborns with BCG (Bacille Calmette Guerin) induces regulatory CD4+ T cells (Tregs), we incubated whole blood of 10 week-old infants, routinely vaccinated at birth, with BCG for 12 hours. We showed that 3 distinct Treg subsets are induced: Interleukin (IL)-10-expressing T-regulatory type 1 (Tr1) cells, transforming growth factor (TGF)-β-expressing T-helper type 3 (Th3) cells, and Foxp3-expressing, presumedly naturally occuring Tregs, or nTregs. IL-10 and TGF-β expression occurred only in specific cells that do not express conventional effector (type 1) cytokines; co-expression of Foxp3+ and type 1 cytokines did rarely occur in the same cells. Depletion of CD127lowCD25high nTregs resulted in modest, but consistent, increases in proliferation induced by purified protein derivative; however, effects of neutralization of TGF-β or IL-10 on proliferation were variable and inconsistent. We hypothesize that protection against childhood tuberculosis afforded by newborn vaccination with BCG will involve a dynamic balance between conventional effector immunity and regulatory CD4+ T cell (Treg) immunity. We further propose that all 3 regulatory CD4+ T cell populations should be assessed in immunogenicity studies of TB vaccines.

SELECTED PUBLICATIONS

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Davids V., Hanekom W., Gelderbloem S.J., Hawkridge A., Hussey G., Sheperd R., Workman L., Soler J., Murray R.A., Ress S.R., and Kaplan G.  Dose-dependent immune response to Mycobacterium bovis BCG vaccination in neonates.  Clin Vaccine Immunol. 2007 Feb;14(2):198-200.