Nanoparticle vaccine offers better protection
Particles that deliver vaccines directly to mucosal surfaces could defend against many infectious diseases.
Many viruses and bacteria infect humans through mucosal surfaces,
such as those in the lungs, gastrointestinal tract and reproductive
tract. To help fight these pathogens, scientists are working on vaccines
that can establish a front line of defense at mucosal surfaces.
Vaccines can be delivered to the lungs via an aerosol spray, but the
lungs often clear away the vaccine before it can provoke an immune
response. To overcome that, MIT engineers have developed a new type of
nanoparticle that protects the vaccine long enough to generate a strong
immune response — not only in the lungs, but also in mucosal surfaces
far from the vaccination site, such as the gastrointestinal and
reproductive tracts.
Such vaccines could help protect against influenza and other respiratory
viruses, or prevent sexually transmitted diseases such as HIV, herpes
simplex virus and human papilloma virus, says Darrell Irvine, an MIT
professor of materials science and engineering and biological
engineering and the leader of the research team. He is also exploring
use of the particles to deliver cancer vaccines.
“This is a good example of a project where the same technology can be
applied in cancer and in infectious disease. It’s a platform technology
to deliver a vaccine of interest,” says Irvine, who is a member of MIT’s
Koch Institute for Integrative Cancer Research and the Ragon Institute
of Massachusetts General Hospital, MIT and Harvard University.
Irvine and colleagues
describe the nanoparticle vaccine in the Sept. 25 issue of
Science Translational Medicine. Lead authors of the paper are recent
PhD recipient Adrienne Li and former MIT postdoc James Moon.
Sturdier vaccines
Only a handful of mucosal vaccines have been approved for human use; the
best-known example is the Sabin polio vaccine, which is given orally and
absorbed in the digestive tract. There is also a flu vaccine delivered
by nasal spray, and mucosal vaccines against cholera, rotavirus and
typhoid fever.
To create better ways of delivering such vaccines, Irvine and his
colleagues built upon a nanoparticle they developed two years ago. The
protein fragments that make up the vaccine are encased in a sphere made
of several layers of lipids that are chemically “stapled” to one
another, making the particles more durable inside the body.
“It’s like going from a soap bubble to a rubber tire. You have something
that’s chemically much more resistant to disassembly,” Irvine says.
This allows the particles to resist disintegration once they reach the
lungs. With this sturdier packaging, the protein vaccine remains in the
lungs long enough for immune cells lining the surface of the lungs to
grab them and deliver them to T cells. Activating T cells is a critical
step for the immune system to form a memory of the vaccine particles so
it will be primed to respond again during an infection.
Stopping the spread of infection
In studies of mice, the researchers found that HIV or cancer antigens
encapsulated in nanoparticles were taken up by immune cells much more
successfully than vaccine delivered to the lungs or under the skin
without being trapped in nanoparticles.
HIV does not infect mice, so to test the immune response generated by
the vaccines, the researchers infected the mice with a version of the
vaccinia virus that was engineered to produce the HIV protein delivered
by the vaccine.
Mice vaccinated with nanoparticles were able to quickly contain the
virus and prevent it from escaping the lungs. Vaccinia virus usually
spreads to the ovaries soon after infection, but the researchers found
that the vaccinia virus in the ovaries of mice vaccinated with
nanoparticles was undetectable, while substantial viral concentrations
were found in mice that received other forms of the vaccine.
Mice that received the nanoparticle vaccine lost a small amount of
weight after infection but then fully recovered, whereas the viral
challenge was 100 percent lethal to mice who received the
non-nanoparticle vaccine.
“Giving the vaccine at the mucosal surface in the nanocapsule form
allowed us to completely block that systemic infection,” Irvine says.
The researchers also found a strong memory T cell presence at distant
mucosal surfaces, including in the digestive and reproductive tracts.
“An important caveat is that although immunity at distant mucus
membranes following vaccination at one mucosal surface has been seen in
humans as well, it’s still being worked out whether the patterns seen in
mice are fully reproduced in humans,” Irvine says. “It might be that
it’s a different mucosal surface that gets stimulated from the lungs or
from oral delivery in humans.”
Melissa Herbst-Kralovetz, an assistant professor of basic medical
sciences at the University of Arizona College of Medicine, says the
nanoparticles are “an exciting and effective strategy for inducing
effector-memory T-cell responses to nonreplicating subunit vaccines
through mucosal vaccination.”
“More research will need to be conducted to determine the delivery
approach to be used in humans, but this vaccination strategy is
particularly important for diseases that may require significant T
cell-mediated protection, such as HIV,” says Herbst-Kralovetz, who was
not part of the research team.
Tumor defense
The particles also hold promise for delivering cancer vaccines, which
stimulate the body’s own immune system to destroy tumors.
To test this, the researchers first implanted the mice with melanoma
tumors that were engineered to express ovalbumin, a protein found in egg
whites. Three days later, they vaccinated the mice with ovalbumin. They
found that mice given the nanoparticle form of the vaccine completely
rejected the tumors, while mice given the uncoated vaccine did not.
Further studies need to be done with more challenging tumor models,
Irvine says. In the future, tests with vaccines targeted to proteins
expressed by cancer cells would be necessary.
The research was funded by the National Cancer Institute, the Ragon
Institute, the Bill and Melinda Gates Foundation, the U.S. Department of
Defense and the National Institutes of Health.
The nanoparticle technology has been patented and licensed to a company
called Vedantra, which is now developing infectious-disease and cancer
vaccines.
News Release; MIT, Sept. 25, 2013