Called the “window of vulnerability,” the first year of a newborn baby’s life is when they are highly susceptible to infectious diseases. This window could narrow or even close completely, if it were possible to vaccinate infants immediately after birth. Instead, two million babies worldwide die each year from infectious diseases before they turn six months old.
“The time of birth is the most reliable point of care for newborns and an efficient opportunity for immunization,” said Northwestern Engineering’sEvan Scott. “The majority of vaccines simply aren’t effective for infants because their immune systems haven’t sufficiently developed.”
Inspired by the BCG (Bacillus Calmette-Guérin) vaccine for tuberculosis, which does work safely and reliably in newborns, Scott and his collaborators are using nanotechnology to make more vaccines that can be administered successfully at the time of birth. They have employed a small molecule that, when delivered into the body via nanoparticles, mimics the type of immune response induced by BCG.
Supported by the National Institutes of Health, National Science Foundation, and Bill and Melinda Gates Foundation, the research was published recently in the Journal of Allergy and Clinical Immunology. Ofer Levy, an infectious diseases specialist at Boston Children’s Hospital, and Jeffrey Hubbell, a biomedical engineer at the University of Chicago, led the study. Scott, assistant professor of biomedical engineering in Northwestern’s McCormick School of Engineering, and David J. Dowling, a postdoctoral researcher in Levy’s laboratory, were the paper’s co-first authors. A member of Northwestern’s Simpson Querrey Institute for BioNanotechnology and Chemistry of Life Processes Institute, Scott was also a corresponding author and led the nanoparticle development.
A developing baby is protected by its mother’s infection-fighting antibodies and antimicrobial agents while still in her womb. After the baby is born, however, it must develop its own immune system, which takes time. Vaccines, which work by activating innate immune responses, fail in babies because their immune systems are suppressed for the first nine months to a year.
“Certain types of inflammation during immune responses can lead to pregnancy loss,” Scott said. “These types of immunity are suppressed during development and remain suppressed after birth for several months, leaving newborns susceptible to many forms of infection.”
The BCG vaccine is routinely given to newborn babies to protect against tuberculosis in most countries outside of the United States and is the most frequently administered vaccine in the world. Only one shot is needed, so boosters and a return visit to the hospital or a medical professional are not required. Patient compliance is a significant barrier for vaccines that require boosters, so limiting the need for boosters can improve vaccine efficacy and protection of the public. Although it has been used in humans since 1921, BCG is still under investigation for why it works so well.
“BCG is commonly used and very safe for infants,” Scott said. “If we can better understand and mimic how it stimulates the immune system, we may be able to make other vaccines more effective for newborns.”
Scott’s collaborator, Ofer Levy, pinpointed a unique target, called toll-like receptor 8, or TLR8, which invokes a similar immune response as BCG in both infants and adults. TLR8 can be stimulated with a synthetic small molecule called CL075. The problem? CL075 is not water soluble and is very difficult to deliver. Furthermore, TLR8 has different responses in humans than in mice, so a special genetically modified (humanized) mouse model is required for testing vaccine formulations that incorporate CL075.
“We haven’t been able to use CL075 in a practical sense,” Scott said. “That’s where nanomaterials come in.”
Scott is an expert in creating nanomaterials that mimic viral structures to target key immune cells during vaccination and immunotherapy. His team screened numerous different nanoparticles with different structures to discover which one would work best. They discovered one nanoparticle in particular, shaped like a vesicle, performed best when delivering the vaccine into cells. They loaded CL075 and a protein component found in tuberculosis into these vesicle-shaped nanoparticles and tested it in a TLR8 humanized mouse model. The result was a success.
“We found that it mimicked BCG really well,” Scott said. “The response gives us an idea of what future vaccines need to do in order to work in newborns and infants.”
That is exactly what is next for the project. Scott and his collaborators plan to incorporate this nano-carrier system into other vaccines to see if and how it works. This could lead to more vaccines that not only work in infants but, like BCG, avoid the need for boosters.
“This is really exciting,” Scott said. “We have the potential to make vaccines safer, easier to deliver, and able to reach a broader pool of the population. We hope to replicate the success of BCG in other vaccines to get rid of that ‘window of vulnerability.’”