The hepatitis B vaccine is one of only three vaccines that are routinely given to newborns in the first days of life. But the current hepatitis B vaccine has limitations: multiple “booster” doses are needed, and it can’t be given to premature babies weighing less than 2 kg.
Annette Scheid, MD, a neonatologist at Brigham and Women’s Hospital, is interested in leveraging infant immune differences to create a better hepatitis B vaccine for newborns. “The reality is that we have to vaccinate several times,” she says. “But we all dream of a vaccine that you give only once.”
An advantageous adjuvant
The answer, oddly enough, may lie in another vaccine given to newborns: Bacillus Calmette–Guérin (BCG). Although BCG vaccine was originally created to protect against tuberculosis infection, some clinical studies have shown that it confers broad, nonspecific resistance to diseases other than tuberculosis. This has interested researchers in its potential as an adjuvant to enhance specific vaccines.
In a study just published in Frontiers in Immunology, Scheid and her collaborators found that the injection of BCG along with the hepatitis B vaccine in preterm and term infants strengthened the immune response to hepatitis B. For example, in both human cord blood cells and live mice, injection of BCG together with the hepatitis B vaccine enhanced the secretion of the cytokine IL1-beta, a cellular messenger important for inducing immune responses, as compared with hepatitis B vaccine alone.
Insight into human immunity and how it varies by age could inform development of broadly protective, single-shot vaccines that are safe and effective in early life. That would be a big win. In cord blood cells from pretern infants, giving BCG along with hepatitis B vaccine induced RNA expression profiles more like those in adults, meaning that key genes involved in immunity and vaccine efficacy that are normally “off” in newborns were turned “on.”
In mice, the immune-strengthening effect of BCG was only observed in newborns, not in adults, indicating that something specific about infant immunity responds to BCG. “We are overcoming immune deficiencies by giving this vaccine,” Scheid says.
When one size doesn’t fit all
Scheid’s project is one of a series of investigations of the Precision Vaccines Program in the Division of Infectious Diseases at Boston Children’s Hospital, which is looking at what makes newborns’ immune systems different, and how to make existing vaccines work better in newborns and other special populations.
“Traditionally, vaccines were approached as ‘one size fits all,’” says program director Ofer Levy, MD, PhD. “But there’s a growing realization that different individuals may respond differently to vaccines based on age, and across factors like sex and geography.”
The program provides a platform for collaborative vaccine development that includes nearly 200 researchers at Boston Children’s and collaborating institutions from academia, government and industry. The BCG project is also part of the Human Immunology Project Consortium (HIPC), a research network established by NIH’s National Institute of Allergy and Infectious Diseases.
A follow-up randomized study, led by Levy, is now enrolling newborns in The Gambia to further test BCG’s capabilities as an adjuvant. At birth, infants will receive no vaccine, hepatitis B vaccine only, BCG vaccine only, or the combined BCG and hepatitis B vaccine. All infants will receive “catch up” immunization at day 7.
Hanno Steen, PhD, director of the Proteomics Center at Boston Children’s Hospital, and his collaborators at the University of British Columbia will then analyze blood samples from all four groups using cutting-edge systems biology techniques.
Using big data and ‘omics’ to help the smallest patients
Since only small draws of blood can be taken from newborns, “we don’t have much material to work with,” says Steen.
But with recently developed technology, one small sample can yield huge amounts of data. Proteomic, transcriptomic, metabolomic and immune function tests can all be done on a few drops of blood.
These “big data,” Levy hopes, will provide insights into the mechanisms behind BCG’s adjuvant-like effect and infant immunity as a whole. Previously, Steen’s laboratory found significant postnatal changes in the abundance of proteins associated with immunity, independent of vaccine stimulation. These changes happen as soon as 24 hours after birth, and the protein networks proliferate rapidly within the first week of life.
Understanding more about the molecular pathways that correlate with enhanced immune responses may allow researchers to develop BCG-like adjuvants and more tailored vaccines for widespread use among newborns.
“The question, ‘what is the impact of a vaccine on the entire inventory of molecules in the body?’ has never been asked in newborns or young infants,” says Levy. “Insight into human immunity and how it varies by age could inform development of broadly protective single-shot vaccines that are safe and effective in early life. That would be a big win.”