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. [1] 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.

Nanoparticle Design, DS-Cav1-I53-50; Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010 [2012-12-15. Lozano et al.]Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010. [1]

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.

Nanoparticle Design, DS-Cav1-I53-50; Neil P. King, PhD, Assistant Professor, Institute for Protein Design. (Credit: UW/IPD)Neil P. King, PhD, Assistant Professor, Institute for Protein Design. (Credit: UW/IPD)

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. [2]

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. [3] 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. [4]

Nanoparticle Design, DS-Cav1-I53-50; Vaccine researchers Brooke Fiala and Neil King in the lab. (Credit: Institute for Protein Design)Vaccine researchers Brooke Fiala and Neil King in the lab. (Credit: Institute for Protein Design)

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. [5] In the last several years, this type of design, has increased the efficiency of vaccines for influenza, HIV, and Epstein-Barr virus.

Nanoparticle Design, DS-Cav1-I53-50; Self-assembling protein nanoparticles in the design of vaccines: flow diagram illustrating how human immunology, B-cell cloning, epitopemapping, structural vaccinology, and nanoparticle design can be combined in order to generate next generation antigen-nanoparticle vaccines. (Credit: Science Direct)Self-assembling protein nanoparticles in the design of vaccines: flow diagram illustrating how human immunology, B-cell cloning, epitopemapping, structural vaccinology, and nanoparticle design can be combined in order to generate next generation antigen-nanoparticle vaccines. [5]

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. [6] 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. [7]

Nanoparticle Design, DS-Cav1-I53-50; Accurate design of megadalton-scale two-component icosahedral protein complexes: Overview of the design method and target architectures [2016-07-22. Science Magazine]Accurate design of megadalton-scale two-component icosahedral protein complexes: Design Process within the I53 Architecture. [6]

  • (A) An icosahedron is outlined with dashed lines, with the five-fold symmetry axes (grey) going through each vertex and three-fold symmetry axes (blue) going through each face of the icosahedron.
  • (B)12 pentamers (grey) and 20 trimers (blue) are aligned along the 5-fold and 3-fold symmetry axes, respectively. Each oligomer possesses two rigid body DOFs, one translational (r) and one rotational (ω) that are systematically sampled to identify configurations.
  • (C) with a large interface between the pentamer and trimer.
  • (D) suitable for protein-protein interface design; only the backbone structure and beta carbons of the oligomers are taken into account during this procedure.
  • (E) Amino acid sequences are designed at the new interface to stabilize the modeled configuration.
  • (F) The I52 architecture comprises 12 pentamers (grey) and 30 dimers (orange) aligned along the five-fold and two-fold icosahedral symmetry axes.
  • (G) The I32 architecture comprises 20 trimers (blue) and 30 dimers (orange) aligned along the three-fold and two-fold icosahedral symmetry axes.

Implications

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.

Nanoparticle Design, DS-Cav1-I53-50; Vaccine candidate DS-Cav1-I53-50 is the result of a fusion between the DS-Cav1 protein and a custom designed nanoparticle scaffold. (Credit: Institute for Protein Design)Vaccine candidate DS-Cav1-I53-50 is the result of a fusion between the DS-Cav1 protein and a custom designed nanoparticle scaffold. (Credit: Institute for Protein Design)

Closing Thoughts

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]

References

  1. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 [2012-12-15. Lozano et al. The Lancet via Science Direct. Volume 380, Issue 9859, 15 December 2012–4 January 2013, Pages 2095-2128] [Alt. Link]
  2. Prefusion F–specific antibodies determine the magnitude of RSV neutralizing activity in human sera [2015-10-14. Joan O. Ngwuta, Man Chen,, Kayvon Modjarrad, M. Gordon Joyce,, Masaru Kanekiyo,, Azad Kumar, Hadi M. Yassine, Syed M. Moin, April M. Killikelly, Gwo-Yu Chuang, Aliaksandr Druz, Ivelin S. Georgiev, Emily J. Rundlet, Mallika Sastry, Guillaume B. E. Stewart-Jones, Yongping Yang, Baoshan Zhang, Martha C. Nason, Cristina Capella, Mark E. Peeples, Julie E. Ledgerwood, Jason S. McLellan, Peter D. Kwong and Barney S. Graham. Science Translational Medicine 14 Oct 2015: Vol. 7, Issue 309, pp. 309ra162]
  3. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention [2012-02-21. Margarita Magro, Vicente Mas, Keith Chappell, Mónica Vázquez, Olga Cano, Daniel Luque, María C. Terrón, José A. Melero, and Concepción Palomo. PNAS February 21, 2012 109 (8) 3089-3094] [Alt. Link]
  4. Pre-fusion RSV F strongly boosts pre-fusion specific neutralizing responses in cattle pre-exposed to bovine RSV [2017-10-20. Ann-Muriel Steff, James Monroe, Kristian Friedrich, Sumana Chandramouli, Thi Lien-Anh Nguyen, Sai Tian, Sarah Vandepaer, Jean-François Toussaint & Andrea Carfi. Nature Communications volume 8, Article number: 1085 (2017)]
  5. Self-assembling protein nanoparticles in the design of vaccines [2015-11-26. Jacinto López-Sagaseta, Enrico Malito, Rino Rappuoli, Matthew J.Bottomley. Computational and Structural Biotechnology Journal. Volume 14, 2016, Pages 58-68 via ScienceDirect] [Alt. Link]
  6. Accurate design of megadalton-scale two-component icosahedral protein complexes [2016-07-22. Jacob B. Bale, Shane Gonen, Yuxi Liu, William Sheffler, Daniel Ellis, Chantz Thomas, Duilio Cascio, Todd O. Yeates, Tamir Gonen, Neil P. King, David Baker. Science 22 Jul 2016: Vol. 353, Issue 6297, pp. 389-394]
  7. 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]

Alison Deshong is a freelance writer with a Master of Science in Biochemistry from the University of California, Davis. She has over eight years of research and writing experience in the biomedical sciences. As a writer, she has a passion for clearly communicating complex concepts to a broad audience and specializes in the topics of science, health, and nutrition.

Alison Deshong is a freelance writer with a Master of Science in Biochemistry from the University of California, Davis. She has over eight years of research and writing experience in the biomedical sciences. As a writer, she has a passion for clearly communicating complex concepts to a broad audience and specializes in the topics of science, health, and nutrition.

Alison Deshong is a freelance writer with a Master of Science in Biochemistry from the University of California, Davis. She has over eight years of research and writing experience in the biomedical sciences. As a writer, she has a passion for clearly communicating complex concepts to a broad audience and specializes in the topics of science, health, and nutrition.

Alison Deshong is a freelance writer with a Master of Science in Biochemistry from the University of California, Davis. She has over eight years of research and writing experience in the biomedical sciences. As a writer, she has a passion for clearly communicating complex concepts to a broad audience and specializes in the topics of science, health, and nutrition.


Gary Karlin Michelson, M.D. and Alya Michelson from the Michelson Medical Research Foundation are proud benefactors of the Institute for Protein Design at the University of Washington. Their generous support advances cutting edge research towards a revolutionary protein design pipeline.

Gary Karlin Michelson, M.D. and Alya Michelson from the Michelson Medical Research Foundation are proud benefactors of the Institute for Protein Design at the University of Washington. Their generous support advances cutting edge research towards a revolutionary protein design pipeline.

Gary Karlin Michelson, M.D. and Alya Michelson from the Michelson Medical Research Foundation are proud benefactors of the Institute for Protein Design at the University of Washington. Their generous support advances cutting edge research towards a revolutionary protein design pipeline.

Gary Karlin Michelson, M.D. and Alya Michelson from the Michelson Medical Research Foundation are proud benefactors of the Institute for Protein Design at the University of Washington. Their generous support advances cutting edge research towards a revolutionary protein design pipeline.