Determining Why Tuberculosis Vaccine Works for Some and Not Others

Willem A. Hanekom, M.B.Ch.B.

University of Miami

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

LAY SUMMARY

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Determining why Tuberculosis Vaccine Works for Some and Not Others

The current tuberculosis (TB) vaccine called BCG has been in use for decades but remains perplexing from many perspectives, including a dearth of significant human research. The BCG vaccine raises adaptive immunity against mycobacteria, the antigen in TB. In South Africa, where tuberculosis is highly prevalent and infants are vaccinated against TB, researchers have found that the vaccine works poorly against lung TB, but affords 80 percent protection against severe TB and TB-associated meningitis in young children. The University of Miami investigators have preliminary evidence that the South African vaccinated infants produce two distinct types of immune T cell reactions to mycobacteria. One T cell type makes a protective cytokine called IFN-g, while the other T cell type produces a suppressive cytokine called IL-10. The researchers hypothesize that the balance between these two types of T cells (protective IFN-g and suppressive IL-10) may be a critical determinant of whether the vaccine protects the infants from developing TB meningitis.

The Miami researchers obtained blood samples from a large number of South African infants who were vaccinated. The researchers will determine the quantities of IFN-g and IL-10 in the infants' blood samples, and will follow the infants to determine whether they get TB and, if so, whether the TB is accompanied by meningitis. Then the investigators will determine whether the balance between these two types of T cell responses differs in the vaccinated infants who nonetheless developed TB with or without meningitis from that in those infants who did not.

ABSTRACT

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Determining Why Tuberculosis Vaccine Works for Some and Not Others

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 A. 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, IL. While a research associate at Rockefeller University in New York, NY, 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 Immunogy 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.