Tuberculosis Clinical Trial
Official title:
Evaluation of the Heterologous Effects of Bacille Calmette-Guérin (BCG) Vaccination in Healthy UK Adults
TB038 is a clinical study to assess the non-specific effects of BCG vaccination and gain a better understanding of how the body's immune system reacts to BCG and in turn potentially prevents infection from other bacteria.
Since 1927, it has been observed that BCG-vaccinated neonates have lower all-cause mortality
rates. This heterologous or non-specific effect within the first 6-12 months of life has
been demonstrated in randomised and observational studies in low income countries with high
childhood mortality rates. The most consistent effect is reduced neonatal mortality due to
fewer cases of neonatal sepsis, respiratory infection and fever. The main limitation of
these studies is the risk of confounding inherent in their cross sectional and observational
designs. It is essential that we determine the cogency of this effect, as potential BCG
replacement vaccines must be non-inferior to BCG in this regard.
There is a plausible rationale that BCG, a replicating mycobacterium, is capable of inducing
non-specific innate immunity, which could induce protection against disease and death from
non-mycobacterial infections early in life. For example, intravesical BCG is an effective
treatment for bladder cancer, an effect presumed to be non-specific and innate. However, our
understanding of the immunological mechanisms involved is incomplete. Data is needed from
robust experiments to quantify any causal relationship between infant survival and BCG
vaccination. Demonstrating an effect of recent BCG vaccination on the growth of common
bacterial pathogens involved in neonatal sepsis, using whole blood in an in-vitro human
model, would provide evidence to support a randomised controlled trial in infants in TB high
burden countries and would impact on public health vaccination scheduling. In addition it
would provide us with an in-vitro model by which to assess future BCG replacement vaccines.
Healthy BCG naïve adults in the UK have been selected for this study because of their low
baseline level of anti-mycobacterial immunity and therefore reduced ability to suppress BCG
growth. Whilst the target population for the heterologous effects of BCG vaccination is
infants, the blood volume required in order to optimise the GIA would not be possible to
collect from infants. Therefore by undertaking this work in healthy BCG naïve UK adults we
can obtain the blood volumes required for this exploratory work in a population of
individuals with a similar background mycobacterial exposure to infants in TB high burden,
low income countries.
Volunteers in this study will receive BCG vaccination at the standard dose of 2-8x10^5 cfu.
BCG SSI containing Mycobacterium bovis strain Danish 1331 is preferred as it is licensed in
the UK for vaccination. However BCG SSI can frequently go into short supply globally with
impact on UK supply. In the event of this occurring, BCG vaccine supplied by the Sii (Serum
institute of India) will be used instead which contains Mycobacterium bovis BCG strain
Moscow 361 I and is on the WHO list of prequalified vaccines. The same strain will be used
for all volunteers.
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Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label
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