transcription factors can bind easier,”
ramping up gene transcription to sup-
port a more robust immune response.
His and other groups have since elu-
cidated similar processes in other com-
ponents of the innate immune system,
such as natural killer cells, Netea adds.
And in a study published earlier this year,
he and colleagues found that BCG vac-
cination in adults appears to shift gene
transcription patterns in immune pre-
cursor cells in the bone marrow to a pro-
gram needed to form a class of leukocytes
known as myeloid cells. Similarly, BCG-
vaccinated newborns quickly boost pro-
duction of neutrophils, a type of myeloid
cell, relative to their unvaccinated peers.^16
(See illustration on page 24.)
Why would an infant’s immune cells
need to be trained, rather than having the
epigenetic marks for a robust immune
response from the start? Netea says he sus-
pects that the answer to that question has to
do with the requirements of human preg-
nancy—namely, that the parent’s body not
reject the fetus. Tamping down the parent’s
immune system during pregnancy could
also affect the fetus’s, he suggests, leading to
babies born vulnerable to infection.
That early vulnerability, counteracted
by live-vaccine immune training, may help
explain the dramatic lowering of all-cause
mortality found with early BCG vaccination
in Guinea-Bissau. But epigenetic effects don’t
appear to be the full story on how BCG—and
potentially other live vaccines—provide non-
specific protections, at least in neonates.
In a study published earlier this year,
a team led by Kollmann and Telethon
Kids Institute researcher Nelly Ame-
nyogbe (and also including Aaby and
Benn) treated some newborn mice with
BCG and then injected fecal bacteria
into their abdomens, and into the abdo-
mens of control animals, to simulate
sepsis. They found that BCG initiated a
process known as emergency granulopoi-
esis, which ramped up the production of
neutrophils in the bone marrow. These
cells “sit in the bone marrow, waiting...
to gobble up bacteria and many other
things,” Kollmann says. “And then, the
moment we induce sepsis in these mice
that have received BCG, [the neutrophils
are] released, go to the site of infection... and knock off these bacteria within
hours of the infectious process starting.”^17
What most struck Kollmann was the
timeline for the emergency granulopoiesis-
based protection: the process began within
hours of BCG inoculation, and the peak of the
neutrophil-based protection came three days
later. It was fast, and it lined up with the find-
ings in the 2011 study that had first drawn
his attention to pathogen-agnostic effects.
The speed of the nonspecific protection also
meshed with results from two other trials that
compared the effects of giving BCG at birth
versus later—namely, that the vaccine pro-
vides dramatic protection that begins almost
immediately after inoculation.
Kollmann says he hopes that the find-
ing of a mechanism to back up the clini-
cal trial data will lead to a more uniform
practice of giving BCG to babies in high-
risk settings immediately after birth.
Longer term, he adds, more research is
needed to better understand BCG’s bene-
ficial effects. “We need to figure out: What
is it about BCG that makes this happen?
Can we formulate this, can we optimize
this, can we make it better, faster?” g
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While observations
of nonspecific effects
are decades old, hints
about the mechanisms
that might explain the
phenomenon have only
begun to emerge.