New IPD Nanoparticle Design Increases RSV Vaccine Potency
A new IPD Nanoparticle Design increases RSV Vaccine Potency
Respiratory syncytial virus represents an enormous public health concern worldwide, particularly in developing countries. However, there are currently no available vaccines that target the virus. Recently, researchers at the Institute for Protein Design have developed a new nanoparticle technology. This new technology has allowed them to engineer a highly potent vaccine that effectively targets respiratory syncytial virus.
The Need for a Respiratory Syncytial Virus Vaccine
Respiratory syncytial virus (RSV) is a common infection. Almost all children will become infected with the virus by the age of three. Reinfection can occur throughout adulthood, but RSV does not pose a threat to healthy adults.
However, infants and children infected with the virus can experience severe respiratory symptoms. In these cases, symptoms include fever, severe cough, wheezing, and difficulty breathing
Aside from malaria, RSV is the second leading cause of infant mortality around the world.  Developing countries are disproportionately burdened by the virus. Researchers have been working to develop a safe and effective vaccine. But unfortunately, there are currently no RSV vaccines available on the market.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010. 
IPD Researchers Target RSV for New Vaccine Design
Researchers in the King lab led by Neil King, a professor at the Institute for Protein Design (IPD), decided to tackle the challenge of engineering an effective RSV vaccine.
The IPD, located at the University of Washington, is a Michelson Medical Research Foundation partially funded initiative. Founded in 2012, the IPD combines the disciplines of biochemistry, molecular biology, structural biology, genomics, and computer science.
By using powerful computational methods, researchers at the IPD can create optimized designer proteins that help solve some of the most pressing challenges of the 21st century. This seemed like an obvious approach to apply to the RSV vaccine.
Laying the Groundwork
Neil King and his colleagues were not the first to approach the problem of designing an RSV vaccine. Researchers have been studying RSV for decades, incrementally laying the groundwork for an effective vaccine.
Most RSV vaccines that have been developed were designed to target RSV F. RSV F is a fusion glycoprotein on the surface of the RSV virus that helps it fuse with host cells. RSV F is also the protein that creates the largest immune response in RSV-infected humans. 
When the RSV virus fuses with a host cell, the RSV F protein undergoes a drastic structural rearrangement. The majority of neutralizing antibodies in RSV-infected humans recognize the more unstable prefusion form of RSV F.  Working with an unstable version of RSV F has complicated the design of a successful vaccine. But researchers were eventually able to engineer a prefusion-stabilized form of RSV F called DS-Cav1. When used as an antigen for vaccination, DS-Cav1 yields a significant neutralizing immune response. 
Building a Better RSV Vaccine at the IPD
DS-Cav1 represented a major breakthrough. But while it’s currently undergoing Phase 1 clinical trials, researchers still don’t know if it will ultimately be effective in humans. The IPD researchers decided to combine new technologies to build upon and improve the design of the DS-Cav1 vaccine.
Immunologists have known that presenting multiple copies of an antigen arranged in a repetitive array can boost the human immune response. Self-assembling proteins have proven to be a successful platform for delivering antigen arrays.  In the last several years, this type of design, has increased the efficiency of vaccines for influenza, HIV, and Epstein-Barr virus.
Self-Assembling Nanoparticle Design Yields Highly Potent RSV Vaccine
At the IPD, the King lab had recently developed a new method for designing customized self-assembling proteins.  They then applied this new technology to the DS-Cav1 vaccine for RSV.
The researchers fused the DS-Cav1 protein to a custom designed nanoparticle scaffold. The scaffold platform facilitated the in vitro formation of a highly structured array consisting of 20 DS-Cav1 trimers.
They named the new vaccine candidate DS-Cav1-I53-50. The new nanoparticle vaccine elicited an immune response nearly 10 times greater than DS-Cav1 on its own in both mice and monkeys. The results were recently published in the journal Cell. 
With such a robust immune response in mice and monkey, there’s a strong possibility that the DS-Cav1-I53-50 vaccine candidate will advance to human clinical trials.
These promising results open the door to a new class of customizable and potent vaccines. Neil King and his team at the IPD are already planning to apply their nanoparticle technology to HIV, malaria, and cancer.
Additionally, the newly designed DS-Cav1-I53-50 displayed a much higher level of stability than DS-Cav1 by itself. This means that nanoparticle vaccines could potentially be less expensive to ship and store—an important feature for vaccines that will likely be in high demand in developing countries.
Once again, the IPD proves that it’s unique multidisciplinary approach is an effective strategy for solving biological problems. This work also offers a robust proof of principle for the nanoparticle technology developed by the King lab. Hopefully this is only the beginning of a series of nanoparticle vaccines to emerge from the King lab and the IPD.
Protein Design named as an Audacious Project [2019-04-16. David Baker. Institute for Protein Design/UW Medicine]
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- Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus [2019-03-07. Jessica Marcandalli, Brooke Fiala, Sebastian Ols, Michela Perotti, Willem de van der Schueren, Joost Snijder, Edgar Hodge, Mark Benhaim, Rashmi Ravichandran, Lauren Carter, Will Sheffler, Livia Brunner, Maria Lawrenz, Patrice Dubois, Antonio Lanzavecchia,Federica Sallusto, Kelly K. Lee, David Veesler, Colin E. Correnti, Lance J. Stewart, David Baker, Karin Loré, Laurent Perez and Neil P. King. Cell 177, 1420–1431.] [Alt. Link]