A Vaccine to Make Vaccines More Effective? HUH?

[Guest guest]

Source: Children's Hospital Boston

Posted: April 24, 2006

Boosting Newborns' Immune Responses: Researchers Identify Agents

That May Make Vaccines Effective At Birth

Newborn babies have immature immune systems, making them highly

vulnerable to severe infections and unable to mount an effective

immune response to most vaccines, thereby frustrating efforts to

protect them. Researchers at Children's Hospital Boston now believe

they have found a way to enhance the immune system at birth and

boost newborns' vaccine responses.

In a study published in the online edition of the journal Blood on

April 25, Ofer Levy, MD, PhD and colleagues in Children's Division

of Infectious Diseases show that the newborn immune system functions

differently than that of adults, but that one portion of the immune

response is fully functional and can be harnessed to boost immunity

in these tiny infants, possibly making infections like respiratory

syncytial virus, pneumococcus, pertussis, HIV and rotavirus much

less of a threat.

For about a decade it's been known that people's first line of

defense against infection is a group of receptors known as Toll-like

receptors (TLRs) on the surface of certain white blood cells.

Functioning like an early radar system, TLRs detect the presence of

invading bacteria and viruses and trigger production of " danger

signals " -- proteins known as cytokines that trigger other immune

cells to mount a defense against the infection. People have 10

different kinds of TLRs, and Levy's team decided to examine how well

they function in newborns by studying white blood cells from their

cord blood.

" We found that when most Toll-like receptors are stimulated,

newborns' immune responses are very impaired, " Levy says. " But there

was one important exception. "

Levy's team, including Harvard graduate Eugenie Suter and senior

author Wessels, MD, showed that one TLR, known as TLR8,

triggered a robust immune response in a group of white blood cells

(called antigen-presenting cells) that is crucial for vaccine

responses. When TLR8 was stimulated by various agents that mimic

viral antigens, the cells produced normal, adult levels of two key

cytokines -- TNF-alpha and IL-12 -- and another immune-system

stimulant, CD40.

" These findings suggest that agents that stimulate TLR8 could be

used to enhance immune responses in newborns, perhaps as adjuvants

given along with vaccines, " Levy says. " We plan to test this

approach in animals, and eventually in human babies. "

Levy notes that the ability to vaccinate newborns -- rather than

wait until they reach 2 months of age -- would provide important

global health benefits. " Birth is a point of contact with healthcare

systems, " he says. " Families may not see a health care provider

after that. From a global health perspective, if you can give a

vaccine at birth, a much higher percentage of the population can be

covered. "

Conceivably, TLR8 stimulators could also be given alone in special

circumstances -- to help a baby fight off an infection in progress,

or as a preventive measure in the event of a disease outbreak or bio-

terrorist threat, Levy adds.

Levy's team is uncovering other differences between the newborn and

adult immune systems that could lead to additional targets for drugs

or vaccines. A related paper, to be published soon in the journal

Pediatric Research, finds that when newborns' TLRs are stimulated

during the first week of life, their white cells' production of the

cytokine IL-6, which inhibits parts of the immune response, is

greater than that in adults.

A third study, to be published in the Journal of Immunology, finds

that newborns' cord blood also has high levels of adenosine,

providing an explanation for newborns' altered immune response:

adenosine alters the physiology of white cells to suppress

production of TNF-alpha (but not of IL-6) when TLRs are stimulated.

When Levy's team used antagonists to inhibit adenosine's activity,

newborns' white blood cells produced normal, adult levels of TNF-

alpha in response to bacterial and viral triggers. " In the future,

we could try to block adenosine in newborn animals to see if this

helps protect against infection, " Levy says.

Levy believes the differences his team has uncovered in newborns'

immune response patterns may serve an evolutionary purpose. Nature

may suppress babies' production of inflammatory cytokines like TNF-

alpha and IL-12 before birth because they can trigger preterm labor,

while increasing production of adenosine and IL-6, which may have a

protective effect on the pregnancy.

In 1999, Levy discovered that newborns are deficient in a natural

antibiotic called bactericidal/permeability-increasing protein

(BPI), produced by white blood cells known as neutrophils. Based on

this discovery, clinical trials are now underway at the University

of Texas Southwestern Medical Center in Dallas to replace the

missing BPI in high-risk newborns with heart conditions who are

undergoing cardiac bypass operations.

" As we better understand the molecular pathways that account for

newborns' susceptibility to infections, we can leverage them to

enhance their immune defenses, " Levy says.

The current study was funded by the National Institutes of Health

and the Trust.