## University of Washington — Protein Design Research (David Baker)

Photo Courtesy of the Institute for Protein Design.

Grant Investigators: Chris Somerville and Heather Youngs

Open Philanthropy recommended a grant of $3,263,750 over five years to the University of Washington to continue to support protein design research, led by Professor David Baker of the Institute for Protein Design. Our scientific research team believes that the outcomes of the research could lead to many helpful applications to improve human health, such as facilitating the creation of improved diagnostic tools and antiviral therapies. This follows our November 2017 support and falls within our work on scientific research, specifically within our interest in advancing human health and wellbeing. ## University of Washington — Universal Influenza Vaccines (Neil King) Open Philanthropy recommended a grant of$3,230,394 over five years to the University of Washington to support work led by Dr. Neil King on the development of universal influenza vaccine candidates. Following our November 2017 support, the researchers in Dr. King’s lab and their colleagues in Dr. Barney Graham’s and Dr. Masaru Kanekiyo’s groups at the National Institutes of Health Vaccine Research Center developed a supraseasonal mosaic nanoparticle vaccine against influenza, which has outperformed commercial influenza vaccines in preclinical trials. This funding is intended to support work to develop additional pan-viral vaccine candidates, with the hope that they will provide potent and broad protection against all influenza A and B viruses.

This falls within our work on scientific research, specifically within our interest in science supporting biosecurity and pandemic preparedness.

## University of Washington — Syphilis Vaccine Development (Lorenzo Giacani)

Grant Investigators: Heather Youngs and Chris Somerville

Open Philanthropy recommended a grant of $816,063 over three years to the University of Washington to support research led by Dr. Lorenzo Giacani that may facilitate the development of a vaccine against syphilis. A leading cause of stillbirth, syphilis is carried by an estimated 36 million people worldwide and infects approximately 11 million people annually.1 Our scientific research team believes that an effective syphilis vaccine could prevent hundreds of thousands of neonatal deaths. This falls within our work on scientific research, specifically within our interest in advancing human health and wellbeing. ## University of Washington — Universal Flu Vaccine and Computational Protein Design (David Baker and Neil King) Award Date: 11/2017 Grant Amount:$11,367,500
Purpose: To support research by Professor David Baker and collaborators on the development of a universal flu vaccine, and to support improved methods for computational design of proteins to treat disease.

Grant Investigators: Chris Somerville and Heather Youngs

The Open Philanthropy Project recommended a grant of $11,367,500 over five years to the University of Washington’s Institute for Protein Design (IPD) to support research on the use of computational protein design to develop a universal influenza vaccine. This work will be led by UW Professor David Baker, Ph.D., and UW Assistant Professor Neil King, Ph.D. In addition, part of this funding is intended to improve the Rosetta molecular modeling and design software originally developed in Baker’s lab. UW Assistant Professor Frank DiMaio, Ph.D., and others will work to improve Rosetta to better predict the properties of proteins, which we believe could lead to many helpful applications in both human and animal health, such as facilitating faster creation of antiviral therapies in the event of a pandemic outbreak. ## The cause Developing a “universal” influenza vaccine has been a long-standing goal of the infectious disease community. Influenza causes an estimated 290,000 – 650,000 deaths each year,1 in addition to carrying pandemic risks, such as the 1918 flu pandemic, which may have killed more than 50 million people. There can be up to 36 million cases of influenza annually in the United States alone, costing the U.S. economy an estimated$87 billion in medical expenses and lost productivity.2

A universal vaccine would protect against all of the many genetic variants of influenza, thereby substantially reducing or eliminating annual deaths associated with the virus, as well as mitigating or even potentially eliminating the risk of influenza pandemics. By administering a universal vaccine early in life, immunity could reach a majority of the world population and potentially eliminate the need for the “seasonal” flu vaccine, thereby reducing the costs and uncertainty associated with current annual influenza vaccination practices.

We are most interested in supporting this work due to its potential to reduce illness and mortality from influenza, as well as the potential to prevent future harm from influenza pandemics. The grant therefore falls within both our scientific research funding category, and our biosecurity and pandemic preparedness focus area.

#### The researchers

The project will be led by Dr. David Baker,3 director of the University of Washington’s Institute for Protein Design, founded in 2012. We consider Dr. Baker and his team exceptionally well-qualified to accomplish the universal influenza vaccine design.

Dr. Baker and colleagues will also collaborate with Dr. Barney Graham, deputy director of the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and chief of the Viral Pathogenesis Laboratory at NIAID. Dr. Graham and his colleagues will be responsible for overseeing evaluation of the safety, immunogenicity, and protective capacity of the universal flu vaccine. NIAID is one of the institutes within the National Institutes of Health, which is funding Dr. Graham’s work.

#### Proposed activities

There are two goals associated with this grant: producing a universal influenza vaccine and improving the Rosetta molecular design and computational chemistry software to better predict properties of proteins.

• Goal 1: Develop a universal flu vaccineDr. Baker and his collaborators will test the hypothesis that immunizing with computationally designed, self-assembling protein nanoparticles displaying highly conserved “epitopes” (fragments of proteins from the flu virus) from all known types of influenza viruses will induce expression of broadly neutralizing antibodies that limit the severity of disease symptoms. Although very rare, such antibodies have been preserved for research after being identified in the serum of people who have previously been infected with influenza virus. When the corresponding genes were expressed in transgenic mice, the antibodies protected the mice against all flu viruses tested.4 We consider this evidence that the approach may work, but we expect the challenge to be developing methods to routinely induce such antibodies with a vaccine in humans. Drs. Baker and King previously used a somewhat similar approach to produce broadly neutralizing antibodies against the respiratory syncytial virus (RSV), which we consider a partial proof of principle. However, because RSV is less variable than influenza, there were fewer challenges to producing that vaccine candidate. Our assessment is that there is an acceptable probability that the proposed experiments will produce a useful flu vaccine that is better than anything currently available.
• Goal 2: Improve the Rosetta molecular design and computational chemistry software to better predict properties of proteinsDr. Baker’s approach to Goal 1 has recently become possible because, during the past several decades, his team and other leading protein chemistry groups have systematically developed sophisticated algorithms that use information about the chemical and physical properties of molecules to facilitate the design and production of proteins with desired three-dimensional structures. This “ab initio” (or “from the beginning”) design approach has made progress but sometimes fails to predict the correct protein structure because some aspects of protein chemistry are not yet completely understood. It is also difficult to make such proteins in a way that accurately resembles the natural three-dimensional structure in the virus, something crucial to a protein’s normal function (for example, generating a robust immune response). Thus, additional research is needed to fully realize the long-term goal of routinely being able to design novel proteins for a wide variety of uses in medicine and industrial applications.Some of this grant funding will therefore support experiments that may facilitate improvements in the ability of the Rosetta software to predict the properties of proteins from their amino acid sequences. Of particular interest, we envision that in the future it may be possible to rapidly design new vaccines or antiviral drugs from the nucleic acid sequences of a new pathogen and to design vaccines that induce immunity against all strains of a pathogen in a relatively short period of time. Drs. Baker and DiMaio have proposed a series of experiments that are designed to improve the predictive power of Rosetta. In brief, they will expand their work in computationally designing self-folding protein scaffolds with shapes customized for applications including binding small molecules and other proteins. They will then systematically synthesize, test, and redesign until the desired properties are achieved. Dr. Baker believes (and we concur) that this approach has a high probability of leading to improvements in our ability to design proteins. We see this approach as timely because it will potentially generate enough information to take advantage of the power of deep learning algorithms to understand protein structure and function.This work is related to Goal 1 above because one of Dr. Baker’s goals is to be able to design therapeutic candidates within weeks of determination of the viral sequence in the event of a viral pandemic outbreak. Therefore, the results are expected to be of general utility. We consider Dr. Baker’s previous work constructing small geometric protein nanoparticles to be particularly suited to mimicking viral structure and antigen presentation.

## Sources

DOCUMENT SOURCE
IPD, David Baker Bio, January 2018 [archive only] Source
Nature Biotechnology, Broad protection against influenza infection by vectored immunoprophylaxis in mice, 2013 Source (archive)
Time, Our Complacency About the Flu is Killing Us, 2018 Source (archive)
World Health Organization Fact Sheet, 2018 Source (archive)