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by Tim Bonfield
A discovery by two scientists at Cincinnati Children’s could lead to the first vaccine that would protect against both rotavirus and norovirus. The viruses are two of the leading causes of severe diarrhea in children, and responsible for hundreds of thousands of deaths each year in developing nations.
This potential leap in vaccine technology is based on new understanding of the P particle, a microscopic vaccine platform developed at Cincinnati Children’s for use against norovirus by Xi Jason Jiang, PhD, and Ming Tan, PhD, researchers in the Division of Infectious Diseases.
“The P particle is very stable and very flexible. It can tolerate the insertion of larger fragments of other antigens, which makes it an excellent platform for vaccine development,” Jiang says.
Their findings were published in the Journal of Virology in 2011. The particle may also be useful against influenza, hepatitis E and other viral diseases. And it could serve as a drug delivery vector to carry therapy agents straight to targeted cells.
These man-made nanoparticles include 24 copies of a protruding (hence the ‘P’ in the name) domain found on the norovirus’ outer surface. The protrusions contain viral receptor binding sites, which make P particles especially effective as vaccine against noroviruses. Jiang and Tan have also developed a smaller P particle that includes just 12 copies of the protruding domain.
In a paper published in PLOS One in April 2013, the researchers demonstrated that P particles produced just as powerful an immune response as did a larger virus-like particle (VLP) now in development as a norovirus-only vaccine (see related story, page 28).
P particles have two major advantages over VLPs: they are easier and cheaper to produce, and they are not damaged when antigens from other viruses are attached to their surface.
“We have identified three major surface loops, plus some minor ones,” Tan says. “We can use these loops to insert foreign antigens of viral pathogens, such as rotavirus, for a dual vaccine. We also could insert a signal peptide that would allow the P particle to target specific tissues.”
The loops are found on each of the 24 P domains of the P particle. When a single antigen or epitope (the part of an antigen that is recognized by the immune system) is inserted into a P domain, it will be duplicated 24 times on the P particle, which increases the potential for inducing a strong immune response.
VLPs also can produce strong immune responses, but they may lack the connection capabilities that allow P particles to serve as dual vaccine platforms. Inserting foreign antigens likely damages VLP formation.
In addition, producing VLPs requires using certain eukaryotic, or membrane-bound, cell factories. This approach can be time-consuming and expensive. P particles can be made by genetically modified E. coli bacteria, a simpler and lower cost process.
“This is particularly important for a low-cost vaccine for developing countries, where they need the vaccine the most,” Tan says.
The technology for producing the first dual vaccine candidate against noroviruses and rotaviruses has been licensed to two pharmaceutical companies: Takeda Vaccine Montana (formerly known as LigoCyte) and PATH Vaccine Solutions, which will take on the next steps of preparing candidate vaccines for human clinical trials. PATH is a non-profit organization based in Seattle. Its efforts to develop a non-replicating rotavirus vaccine are funded primarily by the Bill & Melinda Gates Foundation, which strives to bring vaccines and other health technologies to developing nations.
Jiang and Tan are working with colleagues at Ohio State University to evaluate an influenza vaccine that uses the P particle platform. This vaccine is targeted for use in livestock, but may also have potential as a human vaccine.
Early stage tests also indicate that combining the P particle with a surface antigen of hepatitis E virus (HEV) significantly increases immune response. Researchers report that other vaccines under development include respiratory syncytial virus (RSV), a major cause of respiratory illness in young children, and polio.
“The P particle is a connector,” Jiang says. “It is a platform that can be used to do many things.”
These cryo-electron microscopy (cryo-EM) images illustrate the differences between sub-viral particles of norovirus. The virus-like particle (VLP) is being tested as a potential vaccine, but it is easily damaged when foreign antigens are inserted. The S particle represents the inner capsid shell and has no receptors to interact with a host. Both the larger and smaller P particles were developed at Cincinnati Children’s. With numerous protrusions to serve as antigen binding sites, P particles can serve as useful platforms for dual vaccine development.
These computer-generated ribbon diagrams depict the 3D structure of the binding protrusions that bristle from P particles. Each protrusion has three major “loops” that serve as binding sites for other viral antigens, signal peptides or other useful molecules. When a single epitope (the part of an antigen that is recognized by the immune system) is inserted into a P particle, the epitope will be duplicated 24 times, which increases the potential for creating a strong immune response
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