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 Michael 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.

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The current study was funded by the National Institutes of Health and the Patterson Trust.

Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 11 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: http://www.childrenshospital.org.


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